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NLRC5, a novel role in cardiac fibrosis
G Model BIOPHA 5719 No. of Pages 2
Biomedicine & Pharmacotherapy xxx (2017) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Letter to the Editor NLRC5, a novel role in cardiac fibrosis
The conserved nucleotide-binding oligomerization domain-like receptors (NLRs) exhibits vital functions in the development of immune and inflammatory regulation. NLRC5, as the largest member of NLR family, consisting of an atypical N-terminal caspase recruitment domain (CARD) containing 5, centrally nucleotide-binding domain (NBD) and C-terminal leucine-rich repeat (LRR) region, plays great similar roles in detecting or sensing pathogen-associated molecular patterns (PAMPs) and initiating innate immune responses through triggering diverse signaling pathways [1]. NLRC5 was also identified as a pivotal regulator in the human adaptive immune system by transcriptionally activating major histocompatibility complex class II (MHC-II) genes with a bias for activation of MHC-I promoters [2]. It was demonstrated that NLRC5 could negatively modulate nuclear factor-kB (NF-kB)mediated inflammation by interacting and blocking the phosphorylation of IKKa and IKKß, and it also associated with retinoic acid inducible gene-1 (RIG-I) and melanoma differentiation-associated gene-5 (MDA5) to inhibit type I interferon (IFN) response and cooperatively activated inflammasome signaling pathways via interacting with NLRP3 [3,4]. An interesting study has recently documented that NLRC5 performed a crucial role not only in the immune and inflammatory modulation but also in the process of cardiac fibrosis [5]. Compared to NLRC5 wild type (WT) mice, NLRC5 deficiency mice further promoted the activity of pro-inflammatory cytokines in serum and heart tissue, including interleukin-1ß (IL-1ß), IL-6, IL-18 and tumor necrosis factor-a (TNF-a) induced by high fat feeding. On the contrary, the anti-inflammatory cytokine IL-10 of serum and heart was further decreased in NLRC5-knockout mice compared to WT group, indicating that pro-inflammatory cytokines releasing could be significantly amplified when NLRC5 gene was deficient [5]. Strikingly, the authors firstly revealed that NLRC5 was a vital regulator in cardiac fibrosis. Compared to WT mice, NLRC5 deficiency mice displayed a more enlarged area of myocardial interstitial fibrosis analyzed by the Sirius Red staining facing high fat feeding. High fat feeding induced higher collagen I/ III mRNA levels, a-smooth muscle actin (a-SMA) and transforming growth factor-ß1 (TGF-ß1) protein expressions in NLRC5 deficiency mice. In vitro, the cardiomyocytes isolated from the WT and NLRC5-knockout mice were treated with lipopolysaccharide (LPS), and NLRC5 deficiency greatly potentiated the protein levels of collagen I/III, a-SMA and TGF-ß1 compared to WT group [5]. In summary, these findings indicated that downregulated NLRC5 aggravated the development of cardiac fibrosis under pathological conditions. As a result of inflammatory injury and interstitial fibrosis, cardiac dysfunction was observed in NLRC5-knockout mice proved by increased left ventricular end systolic dimension
(LVESD) and left ventricular end diastolic dimension (LVEDD) as well as decreased left ventricular ejection fraction (LVEF) compared to NLRC5-WT mice [5]. Actually, other studies also confirmed that NLRC5 performed a central role in the progression of fibrosis and might represent a potential target in treatment of fibrotic disease. NLRC5 expression was increased in fibrotic liver tissue both at mRNA and protein levels compared to normal tissue. In cultured hepatic stellate cell (HSC) LX-2, TGF-ß1 induced NLRC5 expression as well as a-SMA and Col1a1, and upregulated NLRC5 sharply improved the expression of a-SMA and Col1a1 but silencing NLRC5 inhibited the fibrotic response, which was associated with the phosphorylation of NF-kB p65 and IkBa [6]. NLRC5 was also related to dermal fibrosis and inhibition of NLRC5 attenuated extracellular matrix (ECM) proteins expression in keloid fibroblasts (KFs) through TGFß1/Smad signaling pathway. Silencing of NLRC5 obviously prevented the expression of collagen I, connective tissue growth factor (CTGF), a-SMA and Smad2/3 phosphorylation in human KFs induced by TGF-ß1 [7]. To date, the clear mechanism of tissue fibrosis remains to be elucidated, while an interesting body of evidence showed that chronic inflammation was one of causes at the onset and development of fibrotic diseases [8]. Based on the previous studies, it may be conceivable that NLRC5 acts as an important molecule in association with inflammation and fibrosis, which subsequently induced the myocardial injury, ventricular remodeling and cardiac dysfunction (Fig. 1). These “dual characteristics” makes it possible that NLRC5 may be a potential therapeutic target for heart failure, although the further study was needed to verify
Fig. 1. Downregulated NLRC5 promoted the myocardial inflammation and cardiac fibrosis, which resulted in cardiac dysfunction.
http://dx.doi.org/10.1016/j.biopha.2017.07.132 0753-3322/© 2017 Published by Elsevier Masson SAS.
Please cite this article in press as: C. Wang, et al., NLRC5, a novel role in cardiac fibrosis, Biomed Pharmacother (2017), http://dx.doi.org/10.1016/ j.biopha.2017.07.132
G Model BIOPHA 5719 No. of Pages 2
2
Letter to the Editor / Biomedicine & Pharmacotherapy xxx (2017) xxx–xxx
whether NLRC5 could trigger the proliferation and differentiation of cardiac fibroblasts, which is considered as the key step of inducing cardiac fibrosis [9]. However, it was somewhat contradictory that NLRC5 deficiency promoted the collagen I/III, a-SMA and TGF-ß1 expression in cardiomyocytes, while silencing NLRC5 inhibited the expression of collagen I, CTGF, a-SMA and Smad2/3 in LX-2 cells and KFs. The confirmed reason of these different results is still unclear. Tissue- or cell-dependent opposite roles may be one of plausible explanations since NLRC5 was broadly expressed in a variety of tissues and cells. For example, NLRC5 inhibited IFN responses by interacting with RIG-I and MDA5 in 293T cells but induced IFN-dependent antiviral responses in HeLaS3 cells [3,10]. On the other hand, different stimulated factors may also contribute to these contradictory findings, so it is essential that more evidences should be explored in the future. Conflict of interest The authors confirm that this article content has no conflicts of interest. Acknowledgements The project was supported by the Natural Science Foundation of Anhui Province (No. 1608085QH196) and the Natural Science Foundation of China (the First Affiliated Hospital of Anhui Medical University, No. 2015KJ21 and No. 2009KJ19). References [1] I. Downs, S. Vijayan, T. Sidiq, et al., CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression, Biofactors 42 (4) (2016) 349–357. [2] A. Neerincx, K. Jakobshagen, O. Utermohlen, et al., The N-terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression, J. Immunol. 193 (6) (2014) 3090–3100.
[3] J. Cui, L. Zhu, X. Xia, et al., NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways, Cell 141 (3) (2010) 483–496. [4] B.K. Davis, R.A. Roberts, M.T. Huang, et al., Cutting edge: NLRC5-dependent activation of the inflammasome, J. Immunol. 186 (3) (2011) 1333–1337. [5] S.R. Ma, X.W. Xie, NLRC5 deficiency promotes myocardial damage induced by high fat diet in mice through activating TLR4/NF-kappaB, Biomed. Pharmacother. 91 (2017) 755–766. [6] X. Liu, Y. Wu, Y. Yang, et al., Role of NLRC5 in progression and reversal of hepatic fibrosis, Toxicol. Appl. Pharmacol. 294 (2016) 43–53. [7] H.L. Ma, X.F. Zhao, G.Z. Chen, et al., Silencing NLRC5 inhibits extracellular matrix expression in keloid fibroblasts via inhibition of transforming growth factorbeta1/Smad signaling pathway, Biomed. Pharmacother. 83 (2016) 1016–1021. [8] P. Kong, P. Christia, N.G. Frangogiannis, The pathogenesis of cardiac fibrosis, Cell Mol. Life Sci. 71 (4) (2014) 549–574. [9] J.G. Travers, F.A. Kamal, J. Robbins, et al., Cardiac fibrosis: the fibroblast awakens, Circ. Res. 118 (6) (2016) 1021–1040. [10] S. Kuenzel, A. Till, M. Winkler, et al., The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses, J. Immunol. 184 (4) (2010) 1990–2000.
Changhui Wang Yifei Tang Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China Dashuai Yang The First Academy of Clinical Medical, Anhui Medical University, Hefei 230032, China Ying Huang* Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China * Corresponding author. E-mail address: [email protected] (Y. Huang). Received 7 June 2017
Please cite this article in press as: C. Wang, et al., NLRC5, a novel role in cardiac fibrosis, Biomed Pharmacother (2017), http://dx.doi.org/10.1016/ j.biopha.2017.07.132
Biomedicine & Pharmacotherapy xxx (2017) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Letter to the Editor NLRC5, a novel role in cardiac fibrosis
The conserved nucleotide-binding oligomerization domain-like receptors (NLRs) exhibits vital functions in the development of immune and inflammatory regulation. NLRC5, as the largest member of NLR family, consisting of an atypical N-terminal caspase recruitment domain (CARD) containing 5, centrally nucleotide-binding domain (NBD) and C-terminal leucine-rich repeat (LRR) region, plays great similar roles in detecting or sensing pathogen-associated molecular patterns (PAMPs) and initiating innate immune responses through triggering diverse signaling pathways [1]. NLRC5 was also identified as a pivotal regulator in the human adaptive immune system by transcriptionally activating major histocompatibility complex class II (MHC-II) genes with a bias for activation of MHC-I promoters [2]. It was demonstrated that NLRC5 could negatively modulate nuclear factor-kB (NF-kB)mediated inflammation by interacting and blocking the phosphorylation of IKKa and IKKß, and it also associated with retinoic acid inducible gene-1 (RIG-I) and melanoma differentiation-associated gene-5 (MDA5) to inhibit type I interferon (IFN) response and cooperatively activated inflammasome signaling pathways via interacting with NLRP3 [3,4]. An interesting study has recently documented that NLRC5 performed a crucial role not only in the immune and inflammatory modulation but also in the process of cardiac fibrosis [5]. Compared to NLRC5 wild type (WT) mice, NLRC5 deficiency mice further promoted the activity of pro-inflammatory cytokines in serum and heart tissue, including interleukin-1ß (IL-1ß), IL-6, IL-18 and tumor necrosis factor-a (TNF-a) induced by high fat feeding. On the contrary, the anti-inflammatory cytokine IL-10 of serum and heart was further decreased in NLRC5-knockout mice compared to WT group, indicating that pro-inflammatory cytokines releasing could be significantly amplified when NLRC5 gene was deficient [5]. Strikingly, the authors firstly revealed that NLRC5 was a vital regulator in cardiac fibrosis. Compared to WT mice, NLRC5 deficiency mice displayed a more enlarged area of myocardial interstitial fibrosis analyzed by the Sirius Red staining facing high fat feeding. High fat feeding induced higher collagen I/ III mRNA levels, a-smooth muscle actin (a-SMA) and transforming growth factor-ß1 (TGF-ß1) protein expressions in NLRC5 deficiency mice. In vitro, the cardiomyocytes isolated from the WT and NLRC5-knockout mice were treated with lipopolysaccharide (LPS), and NLRC5 deficiency greatly potentiated the protein levels of collagen I/III, a-SMA and TGF-ß1 compared to WT group [5]. In summary, these findings indicated that downregulated NLRC5 aggravated the development of cardiac fibrosis under pathological conditions. As a result of inflammatory injury and interstitial fibrosis, cardiac dysfunction was observed in NLRC5-knockout mice proved by increased left ventricular end systolic dimension
(LVESD) and left ventricular end diastolic dimension (LVEDD) as well as decreased left ventricular ejection fraction (LVEF) compared to NLRC5-WT mice [5]. Actually, other studies also confirmed that NLRC5 performed a central role in the progression of fibrosis and might represent a potential target in treatment of fibrotic disease. NLRC5 expression was increased in fibrotic liver tissue both at mRNA and protein levels compared to normal tissue. In cultured hepatic stellate cell (HSC) LX-2, TGF-ß1 induced NLRC5 expression as well as a-SMA and Col1a1, and upregulated NLRC5 sharply improved the expression of a-SMA and Col1a1 but silencing NLRC5 inhibited the fibrotic response, which was associated with the phosphorylation of NF-kB p65 and IkBa [6]. NLRC5 was also related to dermal fibrosis and inhibition of NLRC5 attenuated extracellular matrix (ECM) proteins expression in keloid fibroblasts (KFs) through TGFß1/Smad signaling pathway. Silencing of NLRC5 obviously prevented the expression of collagen I, connective tissue growth factor (CTGF), a-SMA and Smad2/3 phosphorylation in human KFs induced by TGF-ß1 [7]. To date, the clear mechanism of tissue fibrosis remains to be elucidated, while an interesting body of evidence showed that chronic inflammation was one of causes at the onset and development of fibrotic diseases [8]. Based on the previous studies, it may be conceivable that NLRC5 acts as an important molecule in association with inflammation and fibrosis, which subsequently induced the myocardial injury, ventricular remodeling and cardiac dysfunction (Fig. 1). These “dual characteristics” makes it possible that NLRC5 may be a potential therapeutic target for heart failure, although the further study was needed to verify
Fig. 1. Downregulated NLRC5 promoted the myocardial inflammation and cardiac fibrosis, which resulted in cardiac dysfunction.
http://dx.doi.org/10.1016/j.biopha.2017.07.132 0753-3322/© 2017 Published by Elsevier Masson SAS.
Please cite this article in press as: C. Wang, et al., NLRC5, a novel role in cardiac fibrosis, Biomed Pharmacother (2017), http://dx.doi.org/10.1016/ j.biopha.2017.07.132
G Model BIOPHA 5719 No. of Pages 2
2
Letter to the Editor / Biomedicine & Pharmacotherapy xxx (2017) xxx–xxx
whether NLRC5 could trigger the proliferation and differentiation of cardiac fibroblasts, which is considered as the key step of inducing cardiac fibrosis [9]. However, it was somewhat contradictory that NLRC5 deficiency promoted the collagen I/III, a-SMA and TGF-ß1 expression in cardiomyocytes, while silencing NLRC5 inhibited the expression of collagen I, CTGF, a-SMA and Smad2/3 in LX-2 cells and KFs. The confirmed reason of these different results is still unclear. Tissue- or cell-dependent opposite roles may be one of plausible explanations since NLRC5 was broadly expressed in a variety of tissues and cells. For example, NLRC5 inhibited IFN responses by interacting with RIG-I and MDA5 in 293T cells but induced IFN-dependent antiviral responses in HeLaS3 cells [3,10]. On the other hand, different stimulated factors may also contribute to these contradictory findings, so it is essential that more evidences should be explored in the future. Conflict of interest The authors confirm that this article content has no conflicts of interest. Acknowledgements The project was supported by the Natural Science Foundation of Anhui Province (No. 1608085QH196) and the Natural Science Foundation of China (the First Affiliated Hospital of Anhui Medical University, No. 2015KJ21 and No. 2009KJ19). References [1] I. Downs, S. Vijayan, T. Sidiq, et al., CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression, Biofactors 42 (4) (2016) 349–357. [2] A. Neerincx, K. Jakobshagen, O. Utermohlen, et al., The N-terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression, J. Immunol. 193 (6) (2014) 3090–3100.
[3] J. Cui, L. Zhu, X. Xia, et al., NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways, Cell 141 (3) (2010) 483–496. [4] B.K. Davis, R.A. Roberts, M.T. Huang, et al., Cutting edge: NLRC5-dependent activation of the inflammasome, J. Immunol. 186 (3) (2011) 1333–1337. [5] S.R. Ma, X.W. Xie, NLRC5 deficiency promotes myocardial damage induced by high fat diet in mice through activating TLR4/NF-kappaB, Biomed. Pharmacother. 91 (2017) 755–766. [6] X. Liu, Y. Wu, Y. Yang, et al., Role of NLRC5 in progression and reversal of hepatic fibrosis, Toxicol. Appl. Pharmacol. 294 (2016) 43–53. [7] H.L. Ma, X.F. Zhao, G.Z. Chen, et al., Silencing NLRC5 inhibits extracellular matrix expression in keloid fibroblasts via inhibition of transforming growth factorbeta1/Smad signaling pathway, Biomed. Pharmacother. 83 (2016) 1016–1021. [8] P. Kong, P. Christia, N.G. Frangogiannis, The pathogenesis of cardiac fibrosis, Cell Mol. Life Sci. 71 (4) (2014) 549–574. [9] J.G. Travers, F.A. Kamal, J. Robbins, et al., Cardiac fibrosis: the fibroblast awakens, Circ. Res. 118 (6) (2016) 1021–1040. [10] S. Kuenzel, A. Till, M. Winkler, et al., The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses, J. Immunol. 184 (4) (2010) 1990–2000.
Changhui Wang Yifei Tang Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China Dashuai Yang The First Academy of Clinical Medical, Anhui Medical University, Hefei 230032, China Ying Huang* Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China * Corresponding author. E-mail address: [email protected] (Y. Huang). Received 7 June 2017
Please cite this article in press as: C. Wang, et al., NLRC5, a novel role in cardiac fibrosis, Biomed Pharmacother (2017), http://dx.doi.org/10.1016/ j.biopha.2017.07.132