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IL-33, Imprimatur of Adipocyte Thermogenesis

2016; Cell Press; Volume: 166; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2016.07.051

1097-4172

Diane Mathis,

IL-33, ST2, and ILC Pathways

Chawla and colleagues find that interleukin-33 is a critical controller of brown and beige adipocyte thermogenesis. Its primary impact is on the splicing of transcripts encoding uncoupling protein-1, resulting in uncoupled respiration and effective heat generation. Interleukin-33 acts perinatally to ensure adaptive thermogenesis lifelong. Chawla and colleagues find that interleukin-33 is a critical controller of brown and beige adipocyte thermogenesis. Its primary impact is on the splicing of transcripts encoding uncoupling protein-1, resulting in uncoupled respiration and effective heat generation. Interleukin-33 acts perinatally to ensure adaptive thermogenesis lifelong. The maintenance of core body temperature in the face of thermal challenge is a critical aspect of organismal homeostasis in endotherms (Lowell and Spiegelman, 2000Lowell B.B. Spiegelman B.M. Nature. 2000; 404: 652-660Crossref PubMed Scopus (1304) Google Scholar). Exposure to cold elicits strategies to enhance both heat conservation and heat generation. The major means that mammals employ to increase their production of heat are shivering and adaptive thermogenesis. The latter mechanism is primarily the purview of brown and beige adipocytes (Figure 1), wherein uncoupling protein-1 (UCP-1), located within the inner mitochondrial membrane, uncouples oxidative phosphorylation from ATP synthesis, thereby stimulating metabolic respiration and ultimately heat generation. Chawla and colleagues (Odegaard et al., 2016Odegaard J.I. Lee M.-W. Sogawa Y. Bertholet A.M. Locksley R.M. Weinberg D.E. Kirichok Y. Deo R.C. Chawla A. Cell. 2016; 166 (this issue): 841-854Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar) report that mice must synthesize the cytokine interleukin (IL)-33 during a perinatal age window in order for UCP-1 to be properly expressed, for mitochondria to function as needed, and for effective thermogenesis in brown and beige adipocytes throughout life. IL-33, a member of the IL-1 family of cytokines, is a dual-function protein (Molofsky et al., 2015Molofsky A.B. Savage A.K. Locksley R.M. Immunity. 2015; 42: 1005-1019Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar). The full-length version is constitutively expressed in certain epithelial, endothelial, and fibroblastic cells, wherein it binds to chromatin and influences gene expression. A shorter, soluble, version is released and processed by poorly defined processes and binds to a heterodimeric receptor (ST2:IL-1RAcP) displayed mostly on cells of the hematopoietic lineage, impacting their proliferation, survival, differentiation, and immuno-activity. ST2 signals through the MyD88 pathway, mobilizing IRAK1, IRAK4, TRAF6, and NF-κB. Initially, attention was focused on IL-33's ability to promote Type-2 (e.g., allergic or anti-parasitic) immune responses via eosinophils, group-2 innate lymphoid cells (ILC2s), and T helper (Th)-2 lymphocytes. However, more recently, its role in promoting regulatory T cell accumulation and function has garnered much attention. In both contexts, IL-33 acts as an "alarmin," an immediate indicator of tissue stress, such as necrotic (but not apoptotic) cell death or mechanical stretching. Chawla and colleagues (Odegaard et al., 2016Odegaard J.I. Lee M.-W. Sogawa Y. Bertholet A.M. Locksley R.M. Weinberg D.E. Kirichok Y. Deo R.C. Chawla A. Cell. 2016; 166 (this issue): 841-854Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar) find that, when adult mice lacking either IL-33 or ST2 are cold-challenged, interscapular brown adipose tissue (BAT) exhibits histologic abnormalities and thermogenic defects, reflecting a lack of UCP-1. Beige adipocytes increase in representation in inguinal white-adipose tissue (iWAT), but they do not express UCP-1 protein, and their thermogenic capacity is compromised. Parallel results were obtained on perinatal mice as they adapt to life outside the uterus, except that they seem to mobilize other, catabolic, pathways to avoid thermogenic defects in the absence of IL-33 signaling. The lack of functional UCP-1 protein in brown and beige adipocytes is attributed to differential splicing that yielded an abnormal protein. As these effects are found not to depend on ILC2s or T lymphocytes, they are considered to result from a direct impact of IL-33 on adipocytes and/or their immediate precursor cells. Chawla and colleagues (Odegaard et al., 2016Odegaard J.I. Lee M.-W. Sogawa Y. Bertholet A.M. Locksley R.M. Weinberg D.E. Kirichok Y. Deo R.C. Chawla A. Cell. 2016; 166 (this issue): 841-854Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar) draw the interesting conclusion that the IL-33 effects on adipocyte thermogenesis represent an evolutionary adaptation to the mammalian life-style, in preparation for thermal fluctuations once the fetus has emerged from the hermetic environment of the mother's uterus. Evolutionarily, IL-33 appeared at the same time that placental mammals emerged. It is found to be expressed in perinates, and the effects of its loss on the splicing of Ucp1 transcripts and on mitochondrial respiration can be detected during this age window. However, consequent mitochondrial dysfunction accompanied by abnormalities in mitochondrial ultrastructure are not evident until adult life. In addition, injection of soluble, processed IL-33 into adults cannot correct these deficits (although analogous control injections into perinates were not evaluated). The primacy of the perinatal age window would be substantially solidified if confirmed using mice engineered to permit temporal regulation of IL-33 or ST2 expression. This new contribution to the field of immunometabolism offers several novelties. First, the contention that IL-33 affects UCP-1 expression by brown and beige adipocytes while not influencing their differentiation or accumulation diverges from previous conclusions (Lee et al., 2015Lee M.W. Odegaard J.I. Mukundan L. Qiu Y. Molofsky A.B. Nussbaum J.C. Yun K. Locksley R.M. Chawla A. Cell. 2015; 160: 74-87Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, Brestoff et al., 2015Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2015; 519: 242-246Crossref PubMed Scopus (657) Google Scholar), as does the lack of dependence on ILC2s in the current study. Second, IL-33's impact on splicing of Ucp1 transcripts was unexpected and raises the question of how this dual-function cytokine effects the change. Third, while the effects of IL-33 on uncoupled respiration were found to depend on its receptor ST2, surprisingly, they were unaffected by the absence of MyD88, a required downstream signaling element in lymphocytes. Lastly, the concept of perinatal "licensing" of uncoupled respiration in thermogenic adipocytes to enable an effective response to life-long thermal challenges will no doubt shape future work on the function and dysfunction of the metabolic system at the organismal level. There are some perplexing aspects of these new findings. One wonders, first of all, what are the critical IL-33-responding and -producing cells? T lymphocytes and ILCs are usually the major cell types targeted by IL-33, but they seem not to be important in this context. The authors favor a direct impact on fat cells and/or their progenitors, but this notion will be more convincing once ST2 has been demonstrated on the surface of these cells and once pre-adipocyte or adipocyte ablation of ST2 has been observed to abolish IL-33's effects on splicing of Ucp1 transcripts and thermogenesis in adipocytes. In mice, differently from in humans, most IL-33-producing cells in adipose tissue are fibroblastic, and some of these express pre-adipocyte markers (Kolodin et al., 2015Kolodin D. van Panhuys N. Li C. Magnuson A.M. Cipolletta D. Miller C.M. Wagers A. Germain R.N. Benoist C. Mathis D. Cell Metab. 2015; 21: 543-557Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, Kuswanto et al., 2016Kuswanto W. Burzyn D. Panduro M. Wang K.K. Jang Y.C. Wagers A.J. Benoist C. Mathis D. Immunity. 2016; 44: 355-367Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar), raising the possibility of an autocrine loop. Indeed, analysis of recently published RNA-seq data on mural pre-adipocytes (Vishvanath et al., 2016Vishvanath L. MacPherson K.A. Hepler C. Wang Q.A. Shao M. Spurgin S.B. Wang M.Y. Kusminski C.M. Morley T.S. Gupta R.K. Cell Metab. 2016; 23: 350-359Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar) reveals low, but detectable, levels of ST2 transcripts (along with substantial IL-33 transcription). One would be tempted, then, to propose that IL-33's effect on Ucp1 transcript splicing reflects its nuclear function, thereby explaining the lack of dependence on MyD88. However, this scenario fails to explain why mice lacking either IL-33 or ST2 are phenocopies. This issue begs to be resolved. Close intertwining of the metabolic and immune systems is becoming more and more evident. Together with the nervous system, they enforce organismal homeostasis in the face of environmental challenges, whether they are infectious, thermal, dietary, or other. The author wishes to thank Dr. Germán Spallanzani for the analysis of published RNA-seq data. The lab's work on immunometabolism is supported by NIH grant R01 DK092541 and the JPB Foundation. Perinatal Licensing of Thermogenesis by IL-33 and ST2Odegaard et al.CellJuly 21, 2016In BriefA signal from the immune system mediates the activation of thermogenesis during the transition from the in utero maternal environment to postnatal life, allowing animals to maintain their core temperature in cold environments. Full-Text PDF Open Archive