Immunity Review Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation Ari B. Molofsky, 3, 4
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nals that directly repress tissue ILC2s and Tregs during chronic inflammation ( Kearley et al., 2015 ). IL-33 has diverse effects in cancer models. Direct overexpres- sion of IL-33 in neoplasms promoted NK and CD8 + T cell infiltra- tion and restriction of cancer growth and metastasis ( Gao et al., 2015 ). However, IL-33 can signal on cancer cells that themselves express ST2L, thereby promoting survival and metastasis ( Kim
et al., 2014; Levescot et al., 2014; Yu et al., 2015 ). In a model of breast cancer, exogenous IL-33 drove a mixed regulatory/ type 2 immune infiltrate that promoted tumor growth and metas- tasis ( Jovanovic et al., 2014 ). Elevated levels of blood ILC2s were identified in patients with gastric cancer and were associated with a suppressive immune state ( Bie et al., 2014 ). Together, the effects of IL-33 on cancer appear context-specific and might depend on the types of immune cells in the tumor environment, the amount of available IL-33, the amount of sST2 and the tumor cell-intrinsic expression of ST2L. Integrating the Spectrum of IL-33 Activities Understanding of IL-33 biology has evolved and expanded from its predominant role in allergic pathology to unexpected participa- tion in basic physiologic processes connected with development and metabolism, to tissue repair and fibrosis, and to roles in classic inflammation. A framework for conceptualizing the spec- trum of IL-33 biology hypothesizes a stepwise process by which the size of the tissue IL-33 nuclear pool, the presence of support- ing cytokines, and the types of responding cells create a dynamic element embedded within the functionality of tissues ( Figure 3
). Stage 1: Homeostasis The role of IL-33 during tissue homeostasis is most informed from studies in adipose tissue, but similar mechanisms might occur in female reproductive organs and elsewhere ( Figure 2
A). At rest, IL-33 is maintained as a reservoir in the nuclei of certain endothelial and epithelial cells, and perhaps certain fibroblast reticular stromal cells. In response to poorly defined cues, which might be mechanical, hormonal, or metabolic, active IL-33 is translocated to the extracellular space, perhaps through regu- lated secretion or cellular turnover associated with focal areas of cell death. The primary targets of constitutive IL-33 production are likely ILC2s and subsets of Tregs, which are positioned during development and whose activation leads to accumulation of AAMs and eosinophils to create a tissue environment that sup- presses inflammation and promotes a reparative state character- ized by tolerance. At these homeostatic concentrations, effects of IL-33 are restricted to local tissue by the constitutive presence of the decoy receptor, sST2, in serum. Similar pathways might be elicited during localized tissue injury ( Brunner et al., 2011; Duan et al., 2012; Liang et al., 2013; Schiering et al., 2014; Turnquist et al., 2011; Yin et al., 2013 ), where the target of these and related activities might include resident precursor-like stromal cells ( Bur-
zyn et al., 2013; Goh et al., 2013; Heredia et al., 2013; Lee et al., 2015
). While speculative at this time, the ability of IL-33, ILC2, and Treg cells to regulate the tissue regenerative compartment remains an important area for further study. Stage 2: Amplification Migratory helminths, which are highly adapted to their hosts, elicit the second stage of IL-33 biology characterized by in- creased numbers and amounts of IL-33 in involved tissues ( Figure 2 B). This is accompanied by expansion of ST2 + immune cells, particularly ILC2s and Th2 cells, which help to restrict the helminth, but also Treg cells, which repress the pro-inflam- matory effects of chronic infestation and together promote the healing of involved tissue. sST2 levels might increase to contain effects of the expanded IL-33 pool, which can be buffered over many years before pathologic effects of fibrosis and other tissue injuries become apparent. Over time, niches for key precursor cells might become disturbed, such that tissue architecture can no longer be sustained. Tissue tolerance and metabolic al- terations necessary to sustain the massive egg-laying capacity of long-lived helminths might represent adaptations that have co-evolved with these parasites, which are widespread among vertebrates ( Finlay et al., 2014; Maizels et al., 2012; McSorley and Maizels, 2012 ). During allergic pathology, such as asthma and atopic dermatitis, expansion of ILC2s becomes dissociated from Treg stimulation, enabling the activation of adaptive 1012 Immunity 42, June 16, 2015 ª2015 Elsevier Inc. Immunity Review
immunity and associated accumulation of Th2 cells and the development of high-affinity IgE capable of activating mast cells and basophils. Why Treg cells are poorly induced in allergy to environmental allergens remains perplexing but might reflect developmental anomalies related to changes in the early post- natal environment in westernized countries, the so-called ‘‘hy- giene’’ hypothesis. As such, further research investigating the early postnatal development, tissue positioning and differentia- tion of ILC2s and Treg cells might be particularly informative. Indeed, perinatal Treg cells might have specialized properties that endow them with functionalities related to tissue-specific tolerance ( Yang et al., 2015 ). Stage 3: Conversion Inflammatory and infectious conditions associated with loss of epithelial integrity, microbial invasion at damaged barriers, and damage to precursor populations define the third stage of IL-33 ( Figure 2 C). Inflammatory cells such as NK cells, Th1 CD4 + Figure 3. Spectrum of IL-33 Biology A model of the spectrum of IL-33 effects on tissue during beneficial and pathologic immune re- sponses, with IL-33 cellular pools increasing from left to right. (Homeostasis, Blue) IL-33 is present in a restricted subset of cells and cooperates with unknown signals to maintain tissue integrity, limit excess inflammation, and promote tissue adaptation to remodeling and other physiologic stressors. (Amplification, Purple) During acute tissue injury and damage, IL-33 synergizes with other epithelial cytokines and lymphokines to promote tissue homeostasis and repair (stroke, myocardial infarction, wounding). Helminths elicit similar responses. With repetitive tissue damage, IL-33 pools increase, regulatory mechanisms are suppressed, inflammation is amplified, and fibrosis ensues (sclerosis, cirrhosis, allergic dis- ease). (Conversion, Red) Generation of IL-12 and other inflammatory signals promotes IL-33 sig- naling on inflammatory cells that are normally un- responsive, while repressing type 2-associated responses. Activation of this pathway promotes beneficial responses to infection and possibly vaccination, and might support anti-cancer im- mune responses in certain settings. With chronic unresolved inflammation, however, tissue IL-33 increases and ultimately contributes to tissue damage (COPD, autoimmune diseases). T cells, and CD8 + T cells acquire ST2 and thus IL-33 sensitivity in response to IL-12 and other inflammatory media- tors, such that classical immune inflam- matory pathways become engaged, a process we term ‘‘conversion’’ ( Villarreal and Weiner, 2014 ). Regulatory and type 2 responses are also actively repressed by inflammatory signals such as IFN-g ( Molofsky et al., 2015 ). In certain tissues (lymph nodes, spleen), a relative lack of otherwise constitutively ST2 + immune cells might establish permissive condi- tions for acquiring responsiveness to IL-33, which is greatly expanded during the amplification of the fibroblastic reticular cell network and (in human) HEV in the enlarging lymph node. Here, IL-33 be- comes critical in mediating host defense against damaged bar- riers in the setting of bacterial or viral infection. In the chronic phases of inflammation, nuclear pools of IL-33 become greatly expanded in tissue, such that periodic challenges lead to massive release of active IL-33 that overwhelms local sST2 levels and systemic effects of IL-33 begin to dominate. Although such a dramatic shift from type 2-associated to type 1-associated inflammation seems unusual, IL-18, another member of the IL-1 family, can mediate similarly disparate re- sponses ( Fabbi et al., 2015; Smith, 2011; Voehringer, 2012 ). Expression of novel IL-1 family receptors by cells constitutes an economical mechanism to rapidly re-direct conserved signaling networks to alternative effector programs in response to life-threatening challenges. Although much of this model remains conjectural, it provides a framework for organizing the complexities of IL-33 biology while Immunity 42, June 16, 2015 ª2015 Elsevier Inc. 1013 Immunity
Review exposing areas in need of further investigation. Details of IL-33 production and access to the extracellular environment, of sST2 production and regulation, and of factors determining the expression of ST2 on distinct populations of ILC2s and Treg cells remain unclear. The precise role of ST2 on myeloid cells is largely undefined, and the mechanisms by which IL-12 and potentially other signals enable the expansion of ST2 expression and IL-33 responsiveness onto inflammatory cytotoxic cells remain understudied. The next few years will be marked by further un- derstanding of the remarkable spectrum of biologic processes affected by IL-33 and its role in homeostasis, repair, host de- fense, and immunopathology. ACKNOWLEDGMENTS We thank laboratory members for critical review of the manuscript. This work was supported by AI026918, AI030663, HL107202, and K08DK101604 (A.B.M.) from the NIH, the UCSF Diabetes Family Fund (A.B.M.), the Sandler Asthma Basic Research Center at UCSF, and the Howard Hughes Medical Institute. REFERENCES Acton, S.E., Farrugia, A.J., Astarita, J.L., Moura˜o-Sa´, D., Jenkins, R.P., Nye, E., Hooper, S., van Blijswijk, J., Rogers, N.C., Snelgrove, K.J., et al. (2014). Den- dritic cells control fibroblastic reticular network tension and lymph node expansion. Nature 514, 498–502 . Ali, S., Mohs, A., Thomas, M., Klare, J., Ross, R., Schmitz, M.L., and Martin, M.U. (2011). The dual function cytokine IL-33 interacts with the transcription factor NF-kB to dampen NF-kB-stimulated gene transcription. J. Immunol. 187, 1609–1616 . Andrade, M.V., Iwaki, S., Ropert, C., Gazzinelli, R.T., Cunha-Melo, J.R., and Beaven, M.A. (2011). Amplification of cytokine production through synergistic activation of NFAT and AP-1 following stimulation of mast cells with antigen and IL-33. Eur. J. Immunol. 41, 760–772 . Aupperlee, M.D., Zhao, Y., Tan, Y.S., Leipprandt, J.R., Bennett, J., Haslam, S.Z., and Schwartz, R.C. (2014). Epidermal growth factor receptor (EGFR) signaling is a key mediator of hormone-induced leukocyte infiltration in the pu- bertal female mammary gland. Endocrinology 155, 2301–2313 . Baekkevold, E.S., Roussigne´, M., Yamanaka, T., Johansen, F.-E., Jahnsen, F.L., Amalric, F., Brandtzaeg, P., Erard, M., Haraldsen, G., and Girard, J.-P. (2003). Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am. J. Pathol. 163, 69–79 . Bartelt, A., and Heeren, J. (2014). Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 . Bartelt, A., Bruns, O.T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., Kaul, M.G., Tromsdorf, U.I., Weller, H., Waurisch, C., et al. (2011). Brown ad- ipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 . Bartemes, K.R., Iijima, K., Kobayashi, T., Kephart, G.M., McKenzie, A.N., and Kita, H. (2012). IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J. Immunol. 188, 1503–1513 . Baumann, C., Bonilla, W.V., Fro¨hlich, A., Helmstetter, C., Peine, M., Hegazy, A.N., Pinschewer, D.D., and Lo¨hning, M. (2015). T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc. Natl. Acad. Sci. USA 112, 4056–4061 . Beamer, C.A., Girtsman, T.A., Seaver, B.P., Finsaas, K.J., Migliaccio, C.T., Perry, V.K., Rottman, J.B., Smith, D.E., and Holian, A. (2013). IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology 7, 1070– 1081
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