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Hierarchical signaling transduction of the immune and muscle cell crosstalk in muscle regeneration
Cellular Immunology 326 (2018) 2–7
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Research paper
Hierarchical signaling transduction of the immune and muscle cell crosstalk in muscle regeneration
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Wenjun Yang, Ping Hu
State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Immune cells Muscle stem cells Muscle regeneration Cytokines
The muscle regeneration is a complicated bioprocess that involved in many cell types, including necrotic muscle cells, satellite cells, mesenchymal cells, pericytes, immune cells, and other cell types present at the injury site. Immune cells involved in both innate and adaptive immune responses regulate the progress of muscle regeneration. In this review, we discussed the roles of different immune cells in muscle regeneration. The immune cells regulate muscle regeneration through cytokine production, cell-cell contacts, and general immune environment regulation. We also describe the current known mechanism of how immune cells regulating muscle regeneration.
1. Skeletal muscle and satellite cells As the biggest organ in human body, skeletal muscle accounts for about half of the body weight, and is essential for posture maintenance, breathing, locomotion and glucose and lipid metabolism. The loss of muscle tissue in aging or other muscle degenerative diseases causes the mobility loss and mortality [1]. The functional unit of the skeletal muscle is the long multi-nucleated cylindrical muscle fibre. Each myofiber contains hundreds of myonuclei by the fusion of many myoblasts [2]. The muscle fibers are post-mitotic cells unable to divide due to the functions of retinoblastoma protein (RB) [3,4]. They are very slow to turn over with no more than 2% of myonuclei replaced per week under the physiological condition [5]. In everyday life of human beings, the skeletal muscles undergo a variety of injuries including small tears, minor lesions, and even trauma. Skeletal muscles retain the ability to regenerate and remodel upon injury [6,7]. Multiple cell types have been shown to have skeletal muscle differentiation potentials [8]. However, satellite cells (muscle stem cells) are the major player for the regeneration of skeletal muscles. They were first discovered by Alexander Mauro in 1961 [9]. They are mononucleated cells localized between the basement membrane and the sarcolemma of muscle fibers [10–15]. These cells usually remain in quiescent stage and are activated upon injury to regenerate the damaged muscles [13,16–22]. The self-renewal and differentiation are tightly regulated by a group of transcription factors. Pax7 is the key transcription factor, which is required for satellite cell specification and maintenance [23]. It is a
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paired-homeobox transcription factor, and considered as the hall mark of satellite cells [23]. Pax7 plays a dominant role in transcriptional regulation in satellite cells. The Pax7−/− mice are viable but lack functional satellite cells [23]. Pax3 is another member of pairedhomeobox transcription factor. It also plays a critical role in satellite cell specification and maintenance [24,25]. In most cases, Pax3 and Pax7 bind identical DNA motifs and activate a large number of genes involved in muscle stem cell functions [26], though they also have distinct targets [27]. Under normal condition, muscle satellite cells are quiescent and located in protected membrane enclosed niche between the sarcolemma (plasma membrane) and the basal lamina surrounding the myofiber. In response to exercise or trauma, satellite cells are activated and undergo several rounds of divisions. It is called the activation of satellite cells which is a tightly regulated process [26]. After satellite cell activation, a group of transcription factors named myogenic regulatory factors (MRFs), including Myogenic factor 5 (Myf5), muscle-specific regulatory factor 4 (Mrf4), myoblast determination protein (MyoD), and myogenin [28,29], regulates the progressions of satellite cells differentiation. Myf5 and MyoD are the downstream targets of Pax7 [30,31]. Myogenin is one of the target genes of MyoD, which cooperates with Mrf4 to regulate fusion of myotubes and myofiber maturation [32]. Although many great works have been performed to elucidate the mechanism of satellite cell mediated muscle regeneration, many aspects, such as the transition between each stage, the mechanism of satellite cell activation, the orchestration of multiple cell type to achieve timely muscle regeneration, require more investigations. Despite the many regulatory
Corresponding author. E-mail address: [email protected] (P. Hu).
http://dx.doi.org/10.1016/j.cellimm.2017.08.006 Received 12 February 2017; Received in revised form 11 August 2017; Accepted 12 August 2017 Available online 24 August 2017 0008-8749/ © 2017 Published by Elsevier Inc.
Cellular Immunology 326 (2018) 2–7
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homeostasis of the tissues in which they reside. For example, peritoneal cavity macrophages control the production of gut immunoglobulin [49]. The brain-resident macrophages named microglia prune synapses during development [50]. The resident macrophages in muscle originate from bone marrow monocytes [51]. The most popular macrophage classification is M1 and M2. M1 macrophages represent classically activated macrophages, while M2 macrophages refer to alternatively activated macrophages [52]. M1 macrophages are pro-inflammatory, which are induced by IFNγ, TNF-α, and GM-CSF in response to environmental stimuli. M1 macrophages secrete more pro-inflammatory cytokines and chemokines attracting other types of immune cells. M2 macrophages are anti-inflammatory. They are induced by IL-10 and TGF-β. M2 macrophages are mainly involved in tissue repair and remodeling [53]. The monocyte/macrophages have been implicated as key players in skeletal muscle regeneration [51]. Depletion of macrophages leads to impaired muscle regeneration [54,55]. After the first wave of the immune cell infiltration that contains mast cells and neutrophils, the monocytes were subsequently recruited from the peripheral blood to the lesion site. The monocytes were then differentiated into macrophages at the lesion and replace neutrophils to become the major population of immune cells at the injury site. M1 macrophages play several roles during muscle regeneration. They initially function in the removal of the muscle debris at the injury site. Meanwhile, they can attract muscle stem cells to the injured site and stimulate the proliferation of the muscle stem cells [56]. M1 macrophages produce large amount of cytokines such as TNF-α and IL-1β. In addition, they also express inducible nitric oxide synthase (iNOS), which is required for normal muscle repair after injury [57]. Alternatively activated M2 macrophages down-regulate the inflammatory reactions by releasing large amount of anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 to avoid excess tissue damage [55,57,58]. The anti-inflammatory cytokines such as IL-4, IL-10, and IL13 promote the dynamic transition from M1 macrophages to M2 macrophages [59]. Mice carrying specific M2 macrophage inhibition display muscle regeneration defects [60], suggesting that M2 macrophages are required for timely muscle regeneration. Depletion of M1 macrophages and other circulating pro-inflammatory monocytes at the beginning of the muscle injury completely blocks muscle regeneration [54], suggest that macrophages are indispensible for muscle regeneration. While depletion of M2 macrophages at the late stage of muscle regeneration leads to smaller fiber size after muscle regeneration [54], suggesting the function of M2 macrophage in the differentiation of myoblasts and maturation of nascent myofibers.
facets of myogenesis, we will focus on the crosstalk between immune cells and muscle cells and its functions in orchestrating efficient muscle regeneration in this review. 2. Immune cells in muscle regeneration Muscle regeneration process can largely divided into two stages: myolysis and reconstruction [33]. These two stages can be further characterized by the following major events: myofiber necrosis, local inflammation at the injury site, satellite cell activation, migration, and differentiation, new muscle fiber maturation, and new muscle fiber remodeling. Similar to most mammalian tissues, skeletal muscle contains a population of resident immune cells, mainly macrophages and dendritic cells. More types of immune cells, like monocytes, neutrophils, and lymphocytes, infiltrate the injury site or under pathological conditions. The immune system and immune cells play critical regulatory roles during muscle regeneration process. 2.1. Innate immune cells 2.1.1. Complement system, mast cells, and neutrophils The activation of the complement system leads to the production of complement fragments that can play important roles in the inflammatory response. The components C5b-9 of complement system formed the membrane attack complex that can induce a loss in membrane integrity and necrosis of the targeted cells [34]. Complementmediated cytolysis has been reported to play a significant role in muscle diseases, including dermatomyositis [35] and myasthenia gravis [36]. Meanwhile, in the serum of the prolonged exercise group, cleavage products of C3a and C4a were upregulated [37], revealing the involvement of the complement-mediated inflammation in muscles. The initial phase of muscle repair is characterized by necrosis of damaged fibers and activation of immune responses. Complement system serves as the first sensor of the muscle injury. It is rapidly activated in injured muscle, causing infiltration of immune cells to the lesion site [38]. Whether the complement system directly interacts with muscle cells during muscle regeneration remains to be explored. The mast cell degranulation is one of the earliest innate immune system responses that leads to the consequent inflammatory events [39]. Thus, the mast cells represent another early-phase immune cell population involved in muscle damage and repair. Upon the stimulation of the muscle injury, the mast cells are activated to rapidly degranulate and release pro-inflammatory cytokines [40]. Resident mast cells in skeletal muscle are the immediate source of pro-inflammatory cytokines, such as TNFα, IL-1, and histamine, allowing the recruitment of immune cells at the injury site [41]. The immune cells, including more mast cells, neutrophils and other leukocytes were further recruited and infiltrated into the damaged muscle tissues within 30 min and produce more pro-inflammatory cytokines, especially TNF-α [42]. Neutrophils can phagocyte necrotic debris and release variety of factors such as cytokines, enzymes, and oxidative factors [43,44]. Similar to the mast cells, neutrophils are also among the first wave of immune cells to infiltrate the muscle lesions, and are involved in the initiation of pro-inflammatory response following muscle injury. In healthy muscle, neutrophils were recruited by mast cells and show a very quick response after injury to clean up cellular debris [45]. The neutrophils at the muscle lesion then release interleukin 1 (IL-1) and interleukin 8 (IL-8) to induce the macrophage infiltration to the injury site [46].
2.2. Adaptive immune cells 2.2.1. T cells Besides the innate immune cells, the adaptive cells including T cells are also involved in the process of muscle regeneration. T cells play a central role in the cell-mediated immunity. T cells populating the peripheral bold or secondary lymphoid organs were distinguished with the exclusive marker CD4 (CD4+ T cell, T helper) or CD8 (CD8+ T cell, cytotoxic T). During muscle damage, CD8+ T cells were recruited by the macrophages and infiltrated into the injury site [61]. The sustained T-cell presence throughout the regenerative process suggests the involvement of T-cells in skeletal muscle repair [62]. Muscle regeneration was impaired in T cell deficient mice [63]. Transplantation of T cells to the T cell deficient mice can fully rescue the muscle regeneration defects [63]. Further analysis indicates that transplantation of either CD4+ or CD8+ T cells can improve the muscle regeneration in T cell deficient mice [63]. Consistent with these results, CD8+ T cell deficient mice also display defects in muscle regeneration [61]. Transplantation of CD8+ T cell improves the muscle regeneration and reduce the matrix deposit in CD8+ deficient mice [61]. Meanwhile, the infiltration of CD8+ T cells was essential for the
2.1.2. Macrophage Macrophages are mainly derived from blood monocytes and can be recruited to peripheral sites and further induced to differentiate by proinflammatory stimuli [47]. The macrophages constitute very diverse cell populations and have very distinct phenotypes in different tissues [48]. The tissue-resident macrophages play important roles to maintain 3
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How TNFα balances the two aspects of its functions remain to be investigated. IL-6, secreted by both immune cells and muscle cells during skeletal muscle regeneration, is a cytokine with various immune functions [79,80]. Infiltrated monocytes/macrophages express high level of IL-6 after muscle injury. Similar to TNF-α, IL-6 has been demonstrated to play important roles in myogenesis and muscle regeneration [81]. IL-6 can stimulate the migration, proliferation and differentiation of myoblasts to facilitate muscle regeneration [82]. The infiltration of the macrophages also depends on IL-6. The muscle regeneration is impaired in IL-6 deficient mice partially due to the reduced number of infiltrating macrophages at the injury site [83]. Other interleukins including IL-4, IL-8, IL-10, IL-13, are also involved in the muscle regeneration bioprocess [84]. IL-8 can attract neutrophils to the injury site and stimulate their activity at the early stage of muscle regeneration process [85]. IL-10 facilitates the conversion from M1 macrophage to M2 macrophage and promotes muscle regeneration [86]. Loss of IL-10 greatly slowed down muscle regeneration [86]. IL-4 enhances the differentiation of primary myoblasts [54,87]. IL-13 facilitates muscle regeneration by directly promoting muscle stem cell proliferation [88]. IL-4/IL-13 signaling pathway is the critical switch to control muscle resident fibro/adipocyte progenitors (FAPs), which participates in the muscle regeneration process. Activation of IL-4/IL-13 signaling promotes the proliferation of FAPs and inhibits their adipocyte differentiation potentials to reduce fibrosis during muscle regeneration [89]. As described above, the conversion from pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-1β, CCL2, CCL3, CCL4, etc.) to anti-inflammatory cytokines (TGF-β, IL-4, IL-10, IL-13, etc.) is a critical event in muscle regeneration [90,91]. In the early stage of muscle regeneration, the pro-inflammatory response and cytokines leads to the recruitment of immune cells and muscle stem cells to the lesion site. The pro-inflammatory cytokines also stimulate the proliferation of muscle stem cells and inhibiting the differentiation of them. At the late stage of muscle regeneration, the microenvironment is converted to more antiinflammatory. It promotes the differentiation of muscle stem cells.
subsequent recruitment of macrophage to further modulate muscle regeneration [64]. It is well known that the T-cells can secrete plenty of growth factors and cytokines (TNF-α, IFN-γ, IL-4 etc.) that can influence muscle stem cell functions [65,66]. These cytokines are initially produced by the innate immune cells and further released by the adaptive immune cells, especially T-cells. These cytokines are capable of supporting muscle stem cell proliferation and promote muscle regeneration [63]. Recently, Fu et al. identified IL-1α, IL-13, TNF-α, and IFN-γ to be the minimum combination of cytokines to support sustained muscle stem cell expansion both in vitro and in vivo. Long term expansion of muscle stem cells can be achieved in vitro by supplementing muscle stem cells with the combination of the above 4 cytokines. In sharp contrast with the conventional culturing condition which is supplemented with FGF, muscle stem cells cultured with cytokine combinations retain full stemness and are capable of reparation of multiple rounds of muscle injury after transplantation [63]. These results suggest that CD4+ and CD8+ T cells together with the cytokines they secreted play critical roles in the stemness maintenance of muscle stem cells. 2.2.2. Treg cells Treg cells are a subpopulation of T cells specifically expressing CD4, CD25, and Foxp3 [67]. Treg cells are immunosuppressive and can inhibit the induction and proliferation of effector T cells. They are important in regulating immune reactions and protecting individuals from autoimmune disease [68]. Treg cells accumulate in injury site shortly after acute muscle injury [69]. Treg cells can regulate the myeloid populations that infiltrated the damaged tissue, which are important for muscle repair [69]. A specific subpopulation of Treg cells were found in injured muscle, named mTreg. mTreg display distinct protein expression patterns from their counterparts found in other tissues. IL-10, amphiregulin, and plateletderived growth factor (PDGF) are highly expressed in mTreg. These proteins improve myoblast differentiation and promote muscle regeneration [69]. Treg cells also can also modulate muscle regeneration by altering the population of conventional T cells, especially CD8T cells [69]. Co-culturing Treg cells with muscle stem cells can inhibit muscle stem cell differentiation and promote their expansion in vitro [70], suggesting that Treg cells can also modulate the activity of muscle stem cells.
4. Critical pathways for the transmission of the signals between immune cells and muscle cells 4.1. NFκB pathway
3. Cytokines in muscle regeneration NFκB is an ubiquitiously expressed transcription factor that plays vital roles in immune response, cell proliferation, and cell differentiation. NFκB transcription factor family consists of five members: RelA/ p65, RelB, c-Rel, NFκB 1/p50, and NFκB2/p52. The NFκB complex is activated in response to a variety of stimuli, such as infection, including, pro-inflammatory cytokines induction, oxidative stresses and so on [92]. Normally, the NFκB dimers bind to the specific inhibitors—the inhibitors of NF-κB (IκBs) and retained inactivated in the cytoplasm. This inhibitory state can be altered by the IκB kinase (IKK). Activated IKK phosphorylates NFκB-bound IκB proteins. Then, the IκB proteins were ubiquitinated and degradated [93,94]. NFκB can regulate expression of a number of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6). Conversely, various signaling triggers, such as TNFa and IL-1, stimulate the NFκB pathway. After muscle injury, the cytokines including IL-1β, TNFα and IFNγ were released into the immuno-muscular microenvironment. These cytokines can increase NFκB activation in both macrophages and muscle cells. TNFα can activate NFκB in macrophages, which then induces the production of additional proinflammatory factors. Conversely, TNFα can also activate NFκB signaling pathway in myoblasts and promote their proliferation by up-regulating cyclin D1 [95]. The effect of the NFκB pathway in proliferation stimulation is related to the p38 kinase. The suppression of the p38 kinase resulted in the reductions of the myotube formation along with lower levels of myogenin [96]. Despite the beneficial effects
The interactions between a variety of immune cells and muscle stem cells widely exist in the whole process of muscle regeneration [71]. Cytokines are important mediator of these interactions. After muscle injury, mast cells release TNF-α during degranulation, and then neutrophils begin to accumulate in the injured muscle and release more TNF-α [41]. Additionally, the neutrophils produce a large number of pro-inflammatory cytokines such as TNF-α, IL-6, CCL2, CCL17 and some growth factors including FGF, HGF, IGF-I, and VEGF [72]. The infiltrated macrophages secrete cytokines/chemokines such as TNF-α, IL-1β, MCP-1, IFNγ, and IL-6 [54,73,74]. The variety of cytokines together with immune cells constitutes the major part of the microenvironment of muscle regeneration. The pro-inflammatory molecule TNF-α plays several roles in muscle regeneration [75]. TNF-α secreted by neutrophils and M1 macrophages attracts other immune cells and muscle stem cells to the damage site. TNF-α can also induce the generation of iNOS in macrophages that in turn regulates the production of nitric oxide (NO), which further aggravate the muscle damage [56]. TNFα has dual roles in muscle progenitor cell proliferation and differentiation. On one hand, TNFα can activate NFκB in C2C12 myoblasts to inhibit their differentiation [76]. On the other hand, TNFα activates p38 signaling, which in turn promotes the interaction between YY1 and PRC2 to form repressive chromatin structure on Pax7 promoter and facilitate differentiation [77,78]. 4
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W. Yang, P. Hu Fig. 1.
proliferation of myoblasts; JAK1 knockdown enhances the differentiation of myoblasts and inhibits their proliferation; while JAK1 overexpression leads to reduced expression of myogenin and myosin indicating impaired differentiation [100,101]. Knockdown of STAT1 rescues the premature differentiation caused by JAK1 overexpression, suggesting that STAT1 is the downstream transcription factor of JAK1 [100,101]. Together, JAK1-STAT1 signaling prevents the premature differentiation of myoblasts. In contrast, knockdown of JAK2, STAT2 or STAT3 inhibits differentiation, suggesting that JAK2-STAT2/3 signaling pathway promotes myoblast differentiation [102]. Consistently, activation of JAK2-STAT2/3 in vivo under the chronic inflammatory conditions during aging promotes muscle stem cell differentiation and disturbs their normal self-renewal, therefore leading to reduced regeneration potentials [99,103]. Similar to JAK1, knockdown of JAK3 causes precocious differentiation of myoblasts [98]. Different from JAK1, JAK3 prevents premature differentiation of myoblast through STAT3 instead of STAT1 [98]. How each JAK selectively signal to the downstream STAT and push the myogenesis towards different directions remain to be explored.
of NFκB signaling, over-stimulation of NFκB has negative effects on muscles. Persistent stimulation of skeletal muscle fibers with TNF-α and IL-1β results in overstimulation of NFκB and skeletal muscle wasting [97].
4.2. JAK-STAT pathway JAK1, JAK2, JAK3, and TYK2 are members of JAK non-receptor tyrosine kinase family. STATs are downstream transcription factors of JAKs. Nine orthologous of STATs have been identified in mammals named STAT1-9. The JAK-STAT signaling pathway is an important signaling pathway activated by various cytokines, for example IL-6 and IL-4/IL13 [98,81]. As the close correlation between IL-6 and muscle regeneration, the JAK-STAT signaling pathway is expected to be involved in the process [99]. IL-6 activates the JAK-STAT signaling pathway in macrophages to promote the production of other cytokines, which in turn stimulate muscle stem cell proliferation and promote muscle regeneration. Treatment of rat cultured myoblasts with IL-6 results in increased 5
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5. Transcription factors Transcription factors are the final effectors of signaling pathways. About 1500 genes encoding transcription factors are reported to be in the mouse and human genome, representing the second largest gene superfamily [104]. During muscle regeneration, variety of transcription factors are required to drive the process. The functions of transcription factors expressed by the immune cells in muscle regeneration have been investigated. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates the fatty acid metabolism and is highly expressed in macrophages. PPARγ expressed in macrophage can activate the transcription of TGF-β family member GDF3. GDF3 promotes muscle progenitor cell differentiation. PPARγ−/− mice showed a delayed muscle regeneration, indicating that PPARγ was required in muscle repair [105]. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional factor regulating immunity and inflammation [106]. In the pro-inflammatory condition, the HIF-1α expression is up-regulated in the macrophages and promotes the production of more inflammatory cytokines [107]. HIF-1α–deficient macrophages were delayed in invasion to skeletal muscle lesion sites. That results in low level of macrophages infiltration at the injury site. It consequently decreased the capacity of muscle regeneration [108]. Critical transcription factors regulating immune reactions can also regulate the behavior of muscle stem cells and muscle regeneration process. 6. Conclusion Muscle regeneration is a profoundly orchestrated process involved in many cell types. The communication between immune cells and muscle cells accounts for an important part of cell-cell interaction during muscle regeneration (Fig. 1). Disruption of the communications between immune cells and muscle cells impairs muscle regeneration. Now, we just start to unravel partial of the story. Many major questions, such as how the complicated cell-cell communications trigger the expression of key factors for myogenesis; how the conversion of cell population is regulated to couple with the progress of myogenesis, remain to be further investigated. Acknowledgments This work was sponsored by grants from the Ministry of Science and Technology of China – China (2014CB964700, 2017YFA0102700), the National Natural Science Foundation of China – China (31671536 and 91649104), the Key Research Program of the Chinese Academy of Sciences – China (KJZD-EW-L13), CAS-CSTRO cooperative Research Program – China (GJHZ1504), and NN-CAS Research Fund – China (NNCAS-2016-6). References [1] I. Janssen, et al., Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr, J. Appl. Physiol. (1985) 89 (1) (2000) 81–88. [2] B. Mintz, W.W. Baker, Normal mammalian muscle differentiation and gene control of isocitrate dehydrogenase synthesis, Proc. Natl. Acad. Sci. U.S.A. 58 (2) (1967) 592–598. [3] B.G. Novitch, et al., Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle, J. Cell Biol. 135 (2) (1996) 441–456. [4] G. Camarda, et al., A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells, J. Cell Biol. 167 (3) (2004) 417–423. [5] H. Schmalbruch, D.M. Lewis, Dynamics of nuclei of muscle fibers and connective tissue cells in normal and denervated rat muscles, Muscle Nerve 23 (4) (2000) 617–626. [6] J.D. Rosenblatt, A time course study of the isometric contractile properties of rat extensor digitorum longus muscle injected with bupivacaine, Comp. Biochem.
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Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Research paper
Hierarchical signaling transduction of the immune and muscle cell crosstalk in muscle regeneration
T
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Wenjun Yang, Ping Hu
State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Immune cells Muscle stem cells Muscle regeneration Cytokines
The muscle regeneration is a complicated bioprocess that involved in many cell types, including necrotic muscle cells, satellite cells, mesenchymal cells, pericytes, immune cells, and other cell types present at the injury site. Immune cells involved in both innate and adaptive immune responses regulate the progress of muscle regeneration. In this review, we discussed the roles of different immune cells in muscle regeneration. The immune cells regulate muscle regeneration through cytokine production, cell-cell contacts, and general immune environment regulation. We also describe the current known mechanism of how immune cells regulating muscle regeneration.
1. Skeletal muscle and satellite cells As the biggest organ in human body, skeletal muscle accounts for about half of the body weight, and is essential for posture maintenance, breathing, locomotion and glucose and lipid metabolism. The loss of muscle tissue in aging or other muscle degenerative diseases causes the mobility loss and mortality [1]. The functional unit of the skeletal muscle is the long multi-nucleated cylindrical muscle fibre. Each myofiber contains hundreds of myonuclei by the fusion of many myoblasts [2]. The muscle fibers are post-mitotic cells unable to divide due to the functions of retinoblastoma protein (RB) [3,4]. They are very slow to turn over with no more than 2% of myonuclei replaced per week under the physiological condition [5]. In everyday life of human beings, the skeletal muscles undergo a variety of injuries including small tears, minor lesions, and even trauma. Skeletal muscles retain the ability to regenerate and remodel upon injury [6,7]. Multiple cell types have been shown to have skeletal muscle differentiation potentials [8]. However, satellite cells (muscle stem cells) are the major player for the regeneration of skeletal muscles. They were first discovered by Alexander Mauro in 1961 [9]. They are mononucleated cells localized between the basement membrane and the sarcolemma of muscle fibers [10–15]. These cells usually remain in quiescent stage and are activated upon injury to regenerate the damaged muscles [13,16–22]. The self-renewal and differentiation are tightly regulated by a group of transcription factors. Pax7 is the key transcription factor, which is required for satellite cell specification and maintenance [23]. It is a
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paired-homeobox transcription factor, and considered as the hall mark of satellite cells [23]. Pax7 plays a dominant role in transcriptional regulation in satellite cells. The Pax7−/− mice are viable but lack functional satellite cells [23]. Pax3 is another member of pairedhomeobox transcription factor. It also plays a critical role in satellite cell specification and maintenance [24,25]. In most cases, Pax3 and Pax7 bind identical DNA motifs and activate a large number of genes involved in muscle stem cell functions [26], though they also have distinct targets [27]. Under normal condition, muscle satellite cells are quiescent and located in protected membrane enclosed niche between the sarcolemma (plasma membrane) and the basal lamina surrounding the myofiber. In response to exercise or trauma, satellite cells are activated and undergo several rounds of divisions. It is called the activation of satellite cells which is a tightly regulated process [26]. After satellite cell activation, a group of transcription factors named myogenic regulatory factors (MRFs), including Myogenic factor 5 (Myf5), muscle-specific regulatory factor 4 (Mrf4), myoblast determination protein (MyoD), and myogenin [28,29], regulates the progressions of satellite cells differentiation. Myf5 and MyoD are the downstream targets of Pax7 [30,31]. Myogenin is one of the target genes of MyoD, which cooperates with Mrf4 to regulate fusion of myotubes and myofiber maturation [32]. Although many great works have been performed to elucidate the mechanism of satellite cell mediated muscle regeneration, many aspects, such as the transition between each stage, the mechanism of satellite cell activation, the orchestration of multiple cell type to achieve timely muscle regeneration, require more investigations. Despite the many regulatory
Corresponding author. E-mail address: [email protected] (P. Hu).
http://dx.doi.org/10.1016/j.cellimm.2017.08.006 Received 12 February 2017; Received in revised form 11 August 2017; Accepted 12 August 2017 Available online 24 August 2017 0008-8749/ © 2017 Published by Elsevier Inc.
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homeostasis of the tissues in which they reside. For example, peritoneal cavity macrophages control the production of gut immunoglobulin [49]. The brain-resident macrophages named microglia prune synapses during development [50]. The resident macrophages in muscle originate from bone marrow monocytes [51]. The most popular macrophage classification is M1 and M2. M1 macrophages represent classically activated macrophages, while M2 macrophages refer to alternatively activated macrophages [52]. M1 macrophages are pro-inflammatory, which are induced by IFNγ, TNF-α, and GM-CSF in response to environmental stimuli. M1 macrophages secrete more pro-inflammatory cytokines and chemokines attracting other types of immune cells. M2 macrophages are anti-inflammatory. They are induced by IL-10 and TGF-β. M2 macrophages are mainly involved in tissue repair and remodeling [53]. The monocyte/macrophages have been implicated as key players in skeletal muscle regeneration [51]. Depletion of macrophages leads to impaired muscle regeneration [54,55]. After the first wave of the immune cell infiltration that contains mast cells and neutrophils, the monocytes were subsequently recruited from the peripheral blood to the lesion site. The monocytes were then differentiated into macrophages at the lesion and replace neutrophils to become the major population of immune cells at the injury site. M1 macrophages play several roles during muscle regeneration. They initially function in the removal of the muscle debris at the injury site. Meanwhile, they can attract muscle stem cells to the injured site and stimulate the proliferation of the muscle stem cells [56]. M1 macrophages produce large amount of cytokines such as TNF-α and IL-1β. In addition, they also express inducible nitric oxide synthase (iNOS), which is required for normal muscle repair after injury [57]. Alternatively activated M2 macrophages down-regulate the inflammatory reactions by releasing large amount of anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 to avoid excess tissue damage [55,57,58]. The anti-inflammatory cytokines such as IL-4, IL-10, and IL13 promote the dynamic transition from M1 macrophages to M2 macrophages [59]. Mice carrying specific M2 macrophage inhibition display muscle regeneration defects [60], suggesting that M2 macrophages are required for timely muscle regeneration. Depletion of M1 macrophages and other circulating pro-inflammatory monocytes at the beginning of the muscle injury completely blocks muscle regeneration [54], suggest that macrophages are indispensible for muscle regeneration. While depletion of M2 macrophages at the late stage of muscle regeneration leads to smaller fiber size after muscle regeneration [54], suggesting the function of M2 macrophage in the differentiation of myoblasts and maturation of nascent myofibers.
facets of myogenesis, we will focus on the crosstalk between immune cells and muscle cells and its functions in orchestrating efficient muscle regeneration in this review. 2. Immune cells in muscle regeneration Muscle regeneration process can largely divided into two stages: myolysis and reconstruction [33]. These two stages can be further characterized by the following major events: myofiber necrosis, local inflammation at the injury site, satellite cell activation, migration, and differentiation, new muscle fiber maturation, and new muscle fiber remodeling. Similar to most mammalian tissues, skeletal muscle contains a population of resident immune cells, mainly macrophages and dendritic cells. More types of immune cells, like monocytes, neutrophils, and lymphocytes, infiltrate the injury site or under pathological conditions. The immune system and immune cells play critical regulatory roles during muscle regeneration process. 2.1. Innate immune cells 2.1.1. Complement system, mast cells, and neutrophils The activation of the complement system leads to the production of complement fragments that can play important roles in the inflammatory response. The components C5b-9 of complement system formed the membrane attack complex that can induce a loss in membrane integrity and necrosis of the targeted cells [34]. Complementmediated cytolysis has been reported to play a significant role in muscle diseases, including dermatomyositis [35] and myasthenia gravis [36]. Meanwhile, in the serum of the prolonged exercise group, cleavage products of C3a and C4a were upregulated [37], revealing the involvement of the complement-mediated inflammation in muscles. The initial phase of muscle repair is characterized by necrosis of damaged fibers and activation of immune responses. Complement system serves as the first sensor of the muscle injury. It is rapidly activated in injured muscle, causing infiltration of immune cells to the lesion site [38]. Whether the complement system directly interacts with muscle cells during muscle regeneration remains to be explored. The mast cell degranulation is one of the earliest innate immune system responses that leads to the consequent inflammatory events [39]. Thus, the mast cells represent another early-phase immune cell population involved in muscle damage and repair. Upon the stimulation of the muscle injury, the mast cells are activated to rapidly degranulate and release pro-inflammatory cytokines [40]. Resident mast cells in skeletal muscle are the immediate source of pro-inflammatory cytokines, such as TNFα, IL-1, and histamine, allowing the recruitment of immune cells at the injury site [41]. The immune cells, including more mast cells, neutrophils and other leukocytes were further recruited and infiltrated into the damaged muscle tissues within 30 min and produce more pro-inflammatory cytokines, especially TNF-α [42]. Neutrophils can phagocyte necrotic debris and release variety of factors such as cytokines, enzymes, and oxidative factors [43,44]. Similar to the mast cells, neutrophils are also among the first wave of immune cells to infiltrate the muscle lesions, and are involved in the initiation of pro-inflammatory response following muscle injury. In healthy muscle, neutrophils were recruited by mast cells and show a very quick response after injury to clean up cellular debris [45]. The neutrophils at the muscle lesion then release interleukin 1 (IL-1) and interleukin 8 (IL-8) to induce the macrophage infiltration to the injury site [46].
2.2. Adaptive immune cells 2.2.1. T cells Besides the innate immune cells, the adaptive cells including T cells are also involved in the process of muscle regeneration. T cells play a central role in the cell-mediated immunity. T cells populating the peripheral bold or secondary lymphoid organs were distinguished with the exclusive marker CD4 (CD4+ T cell, T helper) or CD8 (CD8+ T cell, cytotoxic T). During muscle damage, CD8+ T cells were recruited by the macrophages and infiltrated into the injury site [61]. The sustained T-cell presence throughout the regenerative process suggests the involvement of T-cells in skeletal muscle repair [62]. Muscle regeneration was impaired in T cell deficient mice [63]. Transplantation of T cells to the T cell deficient mice can fully rescue the muscle regeneration defects [63]. Further analysis indicates that transplantation of either CD4+ or CD8+ T cells can improve the muscle regeneration in T cell deficient mice [63]. Consistent with these results, CD8+ T cell deficient mice also display defects in muscle regeneration [61]. Transplantation of CD8+ T cell improves the muscle regeneration and reduce the matrix deposit in CD8+ deficient mice [61]. Meanwhile, the infiltration of CD8+ T cells was essential for the
2.1.2. Macrophage Macrophages are mainly derived from blood monocytes and can be recruited to peripheral sites and further induced to differentiate by proinflammatory stimuli [47]. The macrophages constitute very diverse cell populations and have very distinct phenotypes in different tissues [48]. The tissue-resident macrophages play important roles to maintain 3
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How TNFα balances the two aspects of its functions remain to be investigated. IL-6, secreted by both immune cells and muscle cells during skeletal muscle regeneration, is a cytokine with various immune functions [79,80]. Infiltrated monocytes/macrophages express high level of IL-6 after muscle injury. Similar to TNF-α, IL-6 has been demonstrated to play important roles in myogenesis and muscle regeneration [81]. IL-6 can stimulate the migration, proliferation and differentiation of myoblasts to facilitate muscle regeneration [82]. The infiltration of the macrophages also depends on IL-6. The muscle regeneration is impaired in IL-6 deficient mice partially due to the reduced number of infiltrating macrophages at the injury site [83]. Other interleukins including IL-4, IL-8, IL-10, IL-13, are also involved in the muscle regeneration bioprocess [84]. IL-8 can attract neutrophils to the injury site and stimulate their activity at the early stage of muscle regeneration process [85]. IL-10 facilitates the conversion from M1 macrophage to M2 macrophage and promotes muscle regeneration [86]. Loss of IL-10 greatly slowed down muscle regeneration [86]. IL-4 enhances the differentiation of primary myoblasts [54,87]. IL-13 facilitates muscle regeneration by directly promoting muscle stem cell proliferation [88]. IL-4/IL-13 signaling pathway is the critical switch to control muscle resident fibro/adipocyte progenitors (FAPs), which participates in the muscle regeneration process. Activation of IL-4/IL-13 signaling promotes the proliferation of FAPs and inhibits their adipocyte differentiation potentials to reduce fibrosis during muscle regeneration [89]. As described above, the conversion from pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-1β, CCL2, CCL3, CCL4, etc.) to anti-inflammatory cytokines (TGF-β, IL-4, IL-10, IL-13, etc.) is a critical event in muscle regeneration [90,91]. In the early stage of muscle regeneration, the pro-inflammatory response and cytokines leads to the recruitment of immune cells and muscle stem cells to the lesion site. The pro-inflammatory cytokines also stimulate the proliferation of muscle stem cells and inhibiting the differentiation of them. At the late stage of muscle regeneration, the microenvironment is converted to more antiinflammatory. It promotes the differentiation of muscle stem cells.
subsequent recruitment of macrophage to further modulate muscle regeneration [64]. It is well known that the T-cells can secrete plenty of growth factors and cytokines (TNF-α, IFN-γ, IL-4 etc.) that can influence muscle stem cell functions [65,66]. These cytokines are initially produced by the innate immune cells and further released by the adaptive immune cells, especially T-cells. These cytokines are capable of supporting muscle stem cell proliferation and promote muscle regeneration [63]. Recently, Fu et al. identified IL-1α, IL-13, TNF-α, and IFN-γ to be the minimum combination of cytokines to support sustained muscle stem cell expansion both in vitro and in vivo. Long term expansion of muscle stem cells can be achieved in vitro by supplementing muscle stem cells with the combination of the above 4 cytokines. In sharp contrast with the conventional culturing condition which is supplemented with FGF, muscle stem cells cultured with cytokine combinations retain full stemness and are capable of reparation of multiple rounds of muscle injury after transplantation [63]. These results suggest that CD4+ and CD8+ T cells together with the cytokines they secreted play critical roles in the stemness maintenance of muscle stem cells. 2.2.2. Treg cells Treg cells are a subpopulation of T cells specifically expressing CD4, CD25, and Foxp3 [67]. Treg cells are immunosuppressive and can inhibit the induction and proliferation of effector T cells. They are important in regulating immune reactions and protecting individuals from autoimmune disease [68]. Treg cells accumulate in injury site shortly after acute muscle injury [69]. Treg cells can regulate the myeloid populations that infiltrated the damaged tissue, which are important for muscle repair [69]. A specific subpopulation of Treg cells were found in injured muscle, named mTreg. mTreg display distinct protein expression patterns from their counterparts found in other tissues. IL-10, amphiregulin, and plateletderived growth factor (PDGF) are highly expressed in mTreg. These proteins improve myoblast differentiation and promote muscle regeneration [69]. Treg cells also can also modulate muscle regeneration by altering the population of conventional T cells, especially CD8T cells [69]. Co-culturing Treg cells with muscle stem cells can inhibit muscle stem cell differentiation and promote their expansion in vitro [70], suggesting that Treg cells can also modulate the activity of muscle stem cells.
4. Critical pathways for the transmission of the signals between immune cells and muscle cells 4.1. NFκB pathway
3. Cytokines in muscle regeneration NFκB is an ubiquitiously expressed transcription factor that plays vital roles in immune response, cell proliferation, and cell differentiation. NFκB transcription factor family consists of five members: RelA/ p65, RelB, c-Rel, NFκB 1/p50, and NFκB2/p52. The NFκB complex is activated in response to a variety of stimuli, such as infection, including, pro-inflammatory cytokines induction, oxidative stresses and so on [92]. Normally, the NFκB dimers bind to the specific inhibitors—the inhibitors of NF-κB (IκBs) and retained inactivated in the cytoplasm. This inhibitory state can be altered by the IκB kinase (IKK). Activated IKK phosphorylates NFκB-bound IκB proteins. Then, the IκB proteins were ubiquitinated and degradated [93,94]. NFκB can regulate expression of a number of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6). Conversely, various signaling triggers, such as TNFa and IL-1, stimulate the NFκB pathway. After muscle injury, the cytokines including IL-1β, TNFα and IFNγ were released into the immuno-muscular microenvironment. These cytokines can increase NFκB activation in both macrophages and muscle cells. TNFα can activate NFκB in macrophages, which then induces the production of additional proinflammatory factors. Conversely, TNFα can also activate NFκB signaling pathway in myoblasts and promote their proliferation by up-regulating cyclin D1 [95]. The effect of the NFκB pathway in proliferation stimulation is related to the p38 kinase. The suppression of the p38 kinase resulted in the reductions of the myotube formation along with lower levels of myogenin [96]. Despite the beneficial effects
The interactions between a variety of immune cells and muscle stem cells widely exist in the whole process of muscle regeneration [71]. Cytokines are important mediator of these interactions. After muscle injury, mast cells release TNF-α during degranulation, and then neutrophils begin to accumulate in the injured muscle and release more TNF-α [41]. Additionally, the neutrophils produce a large number of pro-inflammatory cytokines such as TNF-α, IL-6, CCL2, CCL17 and some growth factors including FGF, HGF, IGF-I, and VEGF [72]. The infiltrated macrophages secrete cytokines/chemokines such as TNF-α, IL-1β, MCP-1, IFNγ, and IL-6 [54,73,74]. The variety of cytokines together with immune cells constitutes the major part of the microenvironment of muscle regeneration. The pro-inflammatory molecule TNF-α plays several roles in muscle regeneration [75]. TNF-α secreted by neutrophils and M1 macrophages attracts other immune cells and muscle stem cells to the damage site. TNF-α can also induce the generation of iNOS in macrophages that in turn regulates the production of nitric oxide (NO), which further aggravate the muscle damage [56]. TNFα has dual roles in muscle progenitor cell proliferation and differentiation. On one hand, TNFα can activate NFκB in C2C12 myoblasts to inhibit their differentiation [76]. On the other hand, TNFα activates p38 signaling, which in turn promotes the interaction between YY1 and PRC2 to form repressive chromatin structure on Pax7 promoter and facilitate differentiation [77,78]. 4
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proliferation of myoblasts; JAK1 knockdown enhances the differentiation of myoblasts and inhibits their proliferation; while JAK1 overexpression leads to reduced expression of myogenin and myosin indicating impaired differentiation [100,101]. Knockdown of STAT1 rescues the premature differentiation caused by JAK1 overexpression, suggesting that STAT1 is the downstream transcription factor of JAK1 [100,101]. Together, JAK1-STAT1 signaling prevents the premature differentiation of myoblasts. In contrast, knockdown of JAK2, STAT2 or STAT3 inhibits differentiation, suggesting that JAK2-STAT2/3 signaling pathway promotes myoblast differentiation [102]. Consistently, activation of JAK2-STAT2/3 in vivo under the chronic inflammatory conditions during aging promotes muscle stem cell differentiation and disturbs their normal self-renewal, therefore leading to reduced regeneration potentials [99,103]. Similar to JAK1, knockdown of JAK3 causes precocious differentiation of myoblasts [98]. Different from JAK1, JAK3 prevents premature differentiation of myoblast through STAT3 instead of STAT1 [98]. How each JAK selectively signal to the downstream STAT and push the myogenesis towards different directions remain to be explored.
of NFκB signaling, over-stimulation of NFκB has negative effects on muscles. Persistent stimulation of skeletal muscle fibers with TNF-α and IL-1β results in overstimulation of NFκB and skeletal muscle wasting [97].
4.2. JAK-STAT pathway JAK1, JAK2, JAK3, and TYK2 are members of JAK non-receptor tyrosine kinase family. STATs are downstream transcription factors of JAKs. Nine orthologous of STATs have been identified in mammals named STAT1-9. The JAK-STAT signaling pathway is an important signaling pathway activated by various cytokines, for example IL-6 and IL-4/IL13 [98,81]. As the close correlation between IL-6 and muscle regeneration, the JAK-STAT signaling pathway is expected to be involved in the process [99]. IL-6 activates the JAK-STAT signaling pathway in macrophages to promote the production of other cytokines, which in turn stimulate muscle stem cell proliferation and promote muscle regeneration. Treatment of rat cultured myoblasts with IL-6 results in increased 5
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5. Transcription factors Transcription factors are the final effectors of signaling pathways. About 1500 genes encoding transcription factors are reported to be in the mouse and human genome, representing the second largest gene superfamily [104]. During muscle regeneration, variety of transcription factors are required to drive the process. The functions of transcription factors expressed by the immune cells in muscle regeneration have been investigated. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates the fatty acid metabolism and is highly expressed in macrophages. PPARγ expressed in macrophage can activate the transcription of TGF-β family member GDF3. GDF3 promotes muscle progenitor cell differentiation. PPARγ−/− mice showed a delayed muscle regeneration, indicating that PPARγ was required in muscle repair [105]. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional factor regulating immunity and inflammation [106]. In the pro-inflammatory condition, the HIF-1α expression is up-regulated in the macrophages and promotes the production of more inflammatory cytokines [107]. HIF-1α–deficient macrophages were delayed in invasion to skeletal muscle lesion sites. That results in low level of macrophages infiltration at the injury site. It consequently decreased the capacity of muscle regeneration [108]. Critical transcription factors regulating immune reactions can also regulate the behavior of muscle stem cells and muscle regeneration process. 6. Conclusion Muscle regeneration is a profoundly orchestrated process involved in many cell types. The communication between immune cells and muscle cells accounts for an important part of cell-cell interaction during muscle regeneration (Fig. 1). Disruption of the communications between immune cells and muscle cells impairs muscle regeneration. Now, we just start to unravel partial of the story. Many major questions, such as how the complicated cell-cell communications trigger the expression of key factors for myogenesis; how the conversion of cell population is regulated to couple with the progress of myogenesis, remain to be further investigated. Acknowledgments This work was sponsored by grants from the Ministry of Science and Technology of China – China (2014CB964700, 2017YFA0102700), the National Natural Science Foundation of China – China (31671536 and 91649104), the Key Research Program of the Chinese Academy of Sciences – China (KJZD-EW-L13), CAS-CSTRO cooperative Research Program – China (GJHZ1504), and NN-CAS Research Fund – China (NNCAS-2016-6). References [1] I. Janssen, et al., Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr, J. Appl. Physiol. (1985) 89 (1) (2000) 81–88. [2] B. Mintz, W.W. Baker, Normal mammalian muscle differentiation and gene control of isocitrate dehydrogenase synthesis, Proc. Natl. Acad. Sci. U.S.A. 58 (2) (1967) 592–598. [3] B.G. Novitch, et al., Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle, J. Cell Biol. 135 (2) (1996) 441–456. [4] G. Camarda, et al., A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells, J. Cell Biol. 167 (3) (2004) 417–423. [5] H. Schmalbruch, D.M. Lewis, Dynamics of nuclei of muscle fibers and connective tissue cells in normal and denervated rat muscles, Muscle Nerve 23 (4) (2000) 617–626. [6] J.D. Rosenblatt, A time course study of the isometric contractile properties of rat extensor digitorum longus muscle injected with bupivacaine, Comp. Biochem.
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