- Email: [email protected]
IL-33 Deals with the Gray Matter
Immunity
Previews IL-33 Deals with the Gray Matter Charle`ne Delmas1,2,3 and Elise Dalmas1,2,3,* 1Institut
National de la Sante´ et de la Recherche Me´dicale (INSERM), Cordeliers Research Center, Paris, France Paris Cite´, Paris, France 3Paris Diderot University, Paris, France *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.005 2Sorbonne
The central nervous system undergoes extensive postnatal synapse remodeling that is critical for the formation of mature neural circuits. In a recent issue of Science, Vainchtein et al. (2018) describe an additional role for astrocyte-derived interleukin-33 (IL-33) in promoting synapse refinement by microglia in the developing brain. The mammalian central nervous system (CNS) relies on precise synaptic circuits that are assembled during brain development through the connections between billions of neurons and support from their glial cells. Glial cells (from the Greek word ‘‘glue’’) consist of three main cell subsets: star-shaped astrocytes that provide an optimally suited milieu for neuronal function, microglia that represent the main resident myeloid immune cells of the brain, and oligodendrocytes that are responsible for the formation of myelin. During the first postnatal weeks, the CNS undergoes extensive synapse remodeling that is critical for the development and maintenance of proper brain circuitry. Therein, the formation of mature neural circuits requires microglia-mediated pruning (i.e., the process of synapse elimination at both the axon and dendrite sites) of excessive synapses and strengthening of appropriate synaptic connections (Paolicelli et al., 2011). Yet, little is known about the specific molecular mechanisms that drive this crucial pruning. In a recent issue of Science, Vainchtein et al. (2018) propose that the interleukin (IL)-1 family cytokine IL-33 is required for synapse homeostasis during early CNS development (Vainchtein et al., 2018). Initially, IL-33 was considered as a potent inducer of type 2 immune responses in the contexts of parasite infections and allergic asthma. It signals via its unique co-receptor ST2 (suppression of tumorigenicity 2; also known as IL1RL1), which is selectively expressed on type 2 immune cells including T helper 2 (Th2) cells, eosinophils, or group 2 innate lymphoid cells. However, more recently, studies have now extended IL-33 biology
to unexpected functions in tissue physiology, beyond its basic immune properties. For example, IL-33 has been shown to license brown and beige adipocyte thermogenesis and to promote insulin secretion by pancreatic islets (Dalmas et al., 2017; Odegaard et al., 2016). Meanwhile, in the brain, most of the studies associate IL-33 signaling with functional recovery in CNS injury mouse models, with a shift toward the regenerative type 2 immunity (Gadani et al., 2015; Luo et al., 2015; Pomeshchik et al., 2015). However, whether IL-33 can also impact the physiological development of the CNS remains unknown. In their study, Vainchtein et al. (2018) first demonstrated endogenous IL-33 expression in the brain correlating with postnatal development, especially in the thalamus and the spinal cord regions. Using two IL-33 reporter mouse models, they showed that IL33 expression was confined to the gray matter, an area of the brain where many types of neurons synapse, and identified astrocytes as the primary source of local IL-33. IL-33producing astrocytes preferentially expressed genes associated with synaptic function and neurotransmitter signaling, suggesting their specific responsiveness to synaptic cues. The thalamic visual nucleus highly expressed IL-33 at the time of eye opening, which was prevented by early enucleation-mediated removal of afferent sensory synapses. These findings clearly suggest that IL33 expression in the postnatal brain coincides with the function of astrocytes during this dynamic period of synaptic development. The authors next investigated the impact of IL-33 deletion on synapse
484 Immunity 47, March 20, 2018 ª 2018 Elsevier Inc.
numbers and circuit activity. Recording intrathalamic circuit oscillatory and neuronal excitatory postsynaptic activities in young adult mice, they showed that IL-33 deficiency was associated with an excessive number of excitatory synapses and overall hypersensitivity in the thalamus compared to wild-type controls. They further showed that both specific deletion of IL-33 in astrocytes and global deletion of Il1rl1 resulted in increased numbers of both excitatory and inhibitory inputs from interneurons onto a-motor neurons (these are known to exit the spinal cord to innervate skeletal muscles for contractions). These abnormal synaptic connections were associated with gray matter tissue stress and deficits in acoustic startle reflex (following a novel and/or intense auditory stimulus), a sensorimotor circuit mediated by a-motor neurons. Thus, IL-33 seems to tightly control synapse numbers and circuit function in the thalamus and spinal cords. The authors next tackled how IL-33 regulates synaptic refinement during brain development. They found that the main IL-33-responsive cell targets in the developing brain were microglia, which mediate synapse pruning through phagocytic engulfment and elimination of synaptic elements. In vitro, recombinant IL-33 promoted immune activation and synaptosome engulfment by purified microglia, consistent with previous work showing that IL-33 stimulates microglial phagocytosis (Yasuoka et al., 2011). Using IL-33-deficient mice, the authors showed that lack of IL-33 altered microglia function with decreased synaptic engulfment compared to controls. Conversely, IL-33 treatment promoted
Immunity
Previews
Figure 1. Astrocyte-Derived IL-33 Stimulates Synapse Elimination by Microglia during CNS Development During the first postnatal weeks, the CNS undergoes extensive synapse remodeling to ensure the formation of mature neural circuits. Excessive and aberrant synaptic connections were sensed by glial astrocytes and triggered the release of IL-33 in the gray matter region. IL-33 in turn signaled to the IL-33 receptor ST2-bearing microglia, promoting their phagocytic abilities to engulf and eliminate redundant synapses. IL-33-mediated control of synaptic homeostasis appears critical for the development of proper brain circuitry.
microglial elimination of excitatory synapses in the mouse thalamus and spinal cord. This effect was partially reversed by the conditional deletion of Il1rl1 in microglia, suggesting that non-microglial ST2-expressing cells are likely to also play a role. Altogether, these findings reveal that IL-33 plays a critical role in regulating synapse number and maturation during CNS development, through the orchestration of a dynamic astrocyte-microglial dialogue as illustrated in Figure 1. The findings that astrocytes can sense and translate aberrant synaptic connections into IL-33 raised several questions. IL-33 is a nuclear-associated cytokine that is normally released by damaged or necrotic cells acting as an ‘‘alarmin,’’ an immediate indicator of tissue stress. It is
relevant to wonder about the nature of the synapse-derived cues that trigger IL33 expression in astrocytes. Whether neurons—or any other neural cells—can produce a yet unknown danger signal to activate adjacent astrocytes in the context of excessive synaptic connections remains to be determined. Moreover, the release mechanism of IL-33 from astrocytes is not addressed, and it is unclear whether astrocytes can secrete IL-33 as an active process or have to engage a cell death pathway. The work of Vainchtein et al. (2018) also identified two subsets of astrocytes in the developing brain on the basis of their IL-33 expression. Studies should further explore the differences in origin, location, and function that distinguish these two populations.
Using global and conditional deletion mouse models, the authors showed that IL-33-mediated synapse remodeling was partially prevented in the absence of microglial ST2. This observation suggests that other ST2-expressing cells could contribute to IL-33 effect. Microglia coexist with multiple immune cells in the CNS including dendritic cells that are also known to directly respond to IL-33 through the ST2 receptor (Mrdjen et al., 2018). Thus, future work is warranted to study whether astrocyte-derived IL-33 also impacts other immune cells and mediates type 2-immune-like responses in the CNS. One evident question remains: does IL33-related astrocyte-microglia communication hold true in humans? The work by Vainchtein et al. was exclusively performed in mouse models, and whether IL-33 plays a role in human brain development requires further examination. Their discovery that IL-33 controls microglial synapse pruning offers clues for exciting research possibilities on pathological conditions characterized by aberrant synaptic connections (similar to those observed during postnatal brain development), including autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder that arises from an imbalance of excitation and inhibition in developing neural systems, resulting in local circuit hyperexcitability and global brain connectivity aberrations in children (Supekar et al., 2013). Although the etiology of the disease is extremely complex, IL-33 appears to be a potential candidate in the altered synapse homeostasis observed in autistic children. The elegant study of Vainchtein et al. (2018) demonstrates conclusively that IL-33 finely tunes synapse remodeling during CNS development. It adds to the growing body of literature exploring the non-immune physiological role of IL-33 (and cytokines in general) in organ function. Today, IL-33 deals with the gray matter, and one can wonder which other tissues it will care for tomorrow.
REFERENCES Dalmas, E., Lehmann, F.M., Dror, E., Wueest, S., Thienel, C., Borsigova, M., Stawiski, M., Traunecker, E., Lucchini, F.C., Dapito, D.H., et al. (2017). Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47, 928–942.e7.
Immunity 47, March 20, 2018 485
Immunity
Previews Gadani, S.P., Walsh, J.T., Smirnov, I., Zheng, J., and Kipnis, J. (2015). The glia-derived alarmin IL33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709.
Odegaard, J.I., Lee, M.W., Sogawa, Y., Bertholet, A.M., Locksley, R.M., Weinberg, D.E., Kirichok, Y., Deo, R.C., and Chawla, A. (2016). Perinatal licensing of thermogenesis by IL-33 and ST2. Cell 166, 841–854.
Supekar, K., Uddin, L.Q., Khouzam, A., Phillips, J., Gaillard, W.D., Kenworthy, L.E., Yerys, B.E., Vaidya, C.J., and Menon, V. (2013). Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep. 5, 738–747.
Luo, Y., Zhou, Y., Xiao, W., Liang, Z., Dai, J., Weng, X., and Wu, X. (2015). Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. Brain Res. 1597, 86–94.
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T.A., Guiducci, E., Dumas, L., et al. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458.
Mrdjen, D., Pavlovic, A., Hartmann, F.J., Schreiner, B., Utz, S.G., Leung, B.P., Lelios, I., Heppner, F.L., Kipnis, J., Merkler, D., et al. (2018). High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6.
Pomeshchik, Y., Kidin, I., Korhonen, P., Savchenko, E., Jaronen, M., Lehtonen, S., Wojciechowski, S., Kanninen, K., Koistinaho, J., and Malm, T. (2015). Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav. Immun. 44, 68–81.
Vainchtein, I.D., Chin, G., Cho, F.S., Kelley, K.W., Miller, J.G., Chien, E.C., Liddelow, S.A., Nguyen, P.T., Nakao-Inoue, H., Dorman, L.C., et al. (2018). Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. Published online February 1, 2018. https://doi.org/10.1126/science.aal3589.
486 Immunity 47, March 20, 2018
Yasuoka, S., Kawanokuchi, J., Parajuli, B., Jin, S., Doi, Y., Noda, M., Sonobe, Y., Takeuchi, H., Mizuno, T., and Suzumura, A. (2011). Production and functions of IL-33 in the central nervous system. Brain Res. 1385, 8–17.
Previews IL-33 Deals with the Gray Matter Charle`ne Delmas1,2,3 and Elise Dalmas1,2,3,* 1Institut
National de la Sante´ et de la Recherche Me´dicale (INSERM), Cordeliers Research Center, Paris, France Paris Cite´, Paris, France 3Paris Diderot University, Paris, France *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.005 2Sorbonne
The central nervous system undergoes extensive postnatal synapse remodeling that is critical for the formation of mature neural circuits. In a recent issue of Science, Vainchtein et al. (2018) describe an additional role for astrocyte-derived interleukin-33 (IL-33) in promoting synapse refinement by microglia in the developing brain. The mammalian central nervous system (CNS) relies on precise synaptic circuits that are assembled during brain development through the connections between billions of neurons and support from their glial cells. Glial cells (from the Greek word ‘‘glue’’) consist of three main cell subsets: star-shaped astrocytes that provide an optimally suited milieu for neuronal function, microglia that represent the main resident myeloid immune cells of the brain, and oligodendrocytes that are responsible for the formation of myelin. During the first postnatal weeks, the CNS undergoes extensive synapse remodeling that is critical for the development and maintenance of proper brain circuitry. Therein, the formation of mature neural circuits requires microglia-mediated pruning (i.e., the process of synapse elimination at both the axon and dendrite sites) of excessive synapses and strengthening of appropriate synaptic connections (Paolicelli et al., 2011). Yet, little is known about the specific molecular mechanisms that drive this crucial pruning. In a recent issue of Science, Vainchtein et al. (2018) propose that the interleukin (IL)-1 family cytokine IL-33 is required for synapse homeostasis during early CNS development (Vainchtein et al., 2018). Initially, IL-33 was considered as a potent inducer of type 2 immune responses in the contexts of parasite infections and allergic asthma. It signals via its unique co-receptor ST2 (suppression of tumorigenicity 2; also known as IL1RL1), which is selectively expressed on type 2 immune cells including T helper 2 (Th2) cells, eosinophils, or group 2 innate lymphoid cells. However, more recently, studies have now extended IL-33 biology
to unexpected functions in tissue physiology, beyond its basic immune properties. For example, IL-33 has been shown to license brown and beige adipocyte thermogenesis and to promote insulin secretion by pancreatic islets (Dalmas et al., 2017; Odegaard et al., 2016). Meanwhile, in the brain, most of the studies associate IL-33 signaling with functional recovery in CNS injury mouse models, with a shift toward the regenerative type 2 immunity (Gadani et al., 2015; Luo et al., 2015; Pomeshchik et al., 2015). However, whether IL-33 can also impact the physiological development of the CNS remains unknown. In their study, Vainchtein et al. (2018) first demonstrated endogenous IL-33 expression in the brain correlating with postnatal development, especially in the thalamus and the spinal cord regions. Using two IL-33 reporter mouse models, they showed that IL33 expression was confined to the gray matter, an area of the brain where many types of neurons synapse, and identified astrocytes as the primary source of local IL-33. IL-33producing astrocytes preferentially expressed genes associated with synaptic function and neurotransmitter signaling, suggesting their specific responsiveness to synaptic cues. The thalamic visual nucleus highly expressed IL-33 at the time of eye opening, which was prevented by early enucleation-mediated removal of afferent sensory synapses. These findings clearly suggest that IL33 expression in the postnatal brain coincides with the function of astrocytes during this dynamic period of synaptic development. The authors next investigated the impact of IL-33 deletion on synapse
484 Immunity 47, March 20, 2018 ª 2018 Elsevier Inc.
numbers and circuit activity. Recording intrathalamic circuit oscillatory and neuronal excitatory postsynaptic activities in young adult mice, they showed that IL-33 deficiency was associated with an excessive number of excitatory synapses and overall hypersensitivity in the thalamus compared to wild-type controls. They further showed that both specific deletion of IL-33 in astrocytes and global deletion of Il1rl1 resulted in increased numbers of both excitatory and inhibitory inputs from interneurons onto a-motor neurons (these are known to exit the spinal cord to innervate skeletal muscles for contractions). These abnormal synaptic connections were associated with gray matter tissue stress and deficits in acoustic startle reflex (following a novel and/or intense auditory stimulus), a sensorimotor circuit mediated by a-motor neurons. Thus, IL-33 seems to tightly control synapse numbers and circuit function in the thalamus and spinal cords. The authors next tackled how IL-33 regulates synaptic refinement during brain development. They found that the main IL-33-responsive cell targets in the developing brain were microglia, which mediate synapse pruning through phagocytic engulfment and elimination of synaptic elements. In vitro, recombinant IL-33 promoted immune activation and synaptosome engulfment by purified microglia, consistent with previous work showing that IL-33 stimulates microglial phagocytosis (Yasuoka et al., 2011). Using IL-33-deficient mice, the authors showed that lack of IL-33 altered microglia function with decreased synaptic engulfment compared to controls. Conversely, IL-33 treatment promoted
Immunity
Previews
Figure 1. Astrocyte-Derived IL-33 Stimulates Synapse Elimination by Microglia during CNS Development During the first postnatal weeks, the CNS undergoes extensive synapse remodeling to ensure the formation of mature neural circuits. Excessive and aberrant synaptic connections were sensed by glial astrocytes and triggered the release of IL-33 in the gray matter region. IL-33 in turn signaled to the IL-33 receptor ST2-bearing microglia, promoting their phagocytic abilities to engulf and eliminate redundant synapses. IL-33-mediated control of synaptic homeostasis appears critical for the development of proper brain circuitry.
microglial elimination of excitatory synapses in the mouse thalamus and spinal cord. This effect was partially reversed by the conditional deletion of Il1rl1 in microglia, suggesting that non-microglial ST2-expressing cells are likely to also play a role. Altogether, these findings reveal that IL-33 plays a critical role in regulating synapse number and maturation during CNS development, through the orchestration of a dynamic astrocyte-microglial dialogue as illustrated in Figure 1. The findings that astrocytes can sense and translate aberrant synaptic connections into IL-33 raised several questions. IL-33 is a nuclear-associated cytokine that is normally released by damaged or necrotic cells acting as an ‘‘alarmin,’’ an immediate indicator of tissue stress. It is
relevant to wonder about the nature of the synapse-derived cues that trigger IL33 expression in astrocytes. Whether neurons—or any other neural cells—can produce a yet unknown danger signal to activate adjacent astrocytes in the context of excessive synaptic connections remains to be determined. Moreover, the release mechanism of IL-33 from astrocytes is not addressed, and it is unclear whether astrocytes can secrete IL-33 as an active process or have to engage a cell death pathway. The work of Vainchtein et al. (2018) also identified two subsets of astrocytes in the developing brain on the basis of their IL-33 expression. Studies should further explore the differences in origin, location, and function that distinguish these two populations.
Using global and conditional deletion mouse models, the authors showed that IL-33-mediated synapse remodeling was partially prevented in the absence of microglial ST2. This observation suggests that other ST2-expressing cells could contribute to IL-33 effect. Microglia coexist with multiple immune cells in the CNS including dendritic cells that are also known to directly respond to IL-33 through the ST2 receptor (Mrdjen et al., 2018). Thus, future work is warranted to study whether astrocyte-derived IL-33 also impacts other immune cells and mediates type 2-immune-like responses in the CNS. One evident question remains: does IL33-related astrocyte-microglia communication hold true in humans? The work by Vainchtein et al. was exclusively performed in mouse models, and whether IL-33 plays a role in human brain development requires further examination. Their discovery that IL-33 controls microglial synapse pruning offers clues for exciting research possibilities on pathological conditions characterized by aberrant synaptic connections (similar to those observed during postnatal brain development), including autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder that arises from an imbalance of excitation and inhibition in developing neural systems, resulting in local circuit hyperexcitability and global brain connectivity aberrations in children (Supekar et al., 2013). Although the etiology of the disease is extremely complex, IL-33 appears to be a potential candidate in the altered synapse homeostasis observed in autistic children. The elegant study of Vainchtein et al. (2018) demonstrates conclusively that IL-33 finely tunes synapse remodeling during CNS development. It adds to the growing body of literature exploring the non-immune physiological role of IL-33 (and cytokines in general) in organ function. Today, IL-33 deals with the gray matter, and one can wonder which other tissues it will care for tomorrow.
REFERENCES Dalmas, E., Lehmann, F.M., Dror, E., Wueest, S., Thienel, C., Borsigova, M., Stawiski, M., Traunecker, E., Lucchini, F.C., Dapito, D.H., et al. (2017). Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47, 928–942.e7.
Immunity 47, March 20, 2018 485
Immunity
Previews Gadani, S.P., Walsh, J.T., Smirnov, I., Zheng, J., and Kipnis, J. (2015). The glia-derived alarmin IL33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709.
Odegaard, J.I., Lee, M.W., Sogawa, Y., Bertholet, A.M., Locksley, R.M., Weinberg, D.E., Kirichok, Y., Deo, R.C., and Chawla, A. (2016). Perinatal licensing of thermogenesis by IL-33 and ST2. Cell 166, 841–854.
Supekar, K., Uddin, L.Q., Khouzam, A., Phillips, J., Gaillard, W.D., Kenworthy, L.E., Yerys, B.E., Vaidya, C.J., and Menon, V. (2013). Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep. 5, 738–747.
Luo, Y., Zhou, Y., Xiao, W., Liang, Z., Dai, J., Weng, X., and Wu, X. (2015). Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. Brain Res. 1597, 86–94.
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T.A., Guiducci, E., Dumas, L., et al. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458.
Mrdjen, D., Pavlovic, A., Hartmann, F.J., Schreiner, B., Utz, S.G., Leung, B.P., Lelios, I., Heppner, F.L., Kipnis, J., Merkler, D., et al. (2018). High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6.
Pomeshchik, Y., Kidin, I., Korhonen, P., Savchenko, E., Jaronen, M., Lehtonen, S., Wojciechowski, S., Kanninen, K., Koistinaho, J., and Malm, T. (2015). Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav. Immun. 44, 68–81.
Vainchtein, I.D., Chin, G., Cho, F.S., Kelley, K.W., Miller, J.G., Chien, E.C., Liddelow, S.A., Nguyen, P.T., Nakao-Inoue, H., Dorman, L.C., et al. (2018). Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. Published online February 1, 2018. https://doi.org/10.1126/science.aal3589.
486 Immunity 47, March 20, 2018
Yasuoka, S., Kawanokuchi, J., Parajuli, B., Jin, S., Doi, Y., Noda, M., Sonobe, Y., Takeuchi, H., Mizuno, T., and Suzumura, A. (2011). Production and functions of IL-33 in the central nervous system. Brain Res. 1385, 8–17.