ABSTRACT
Interleukin-33 (IL-33) - a member of the IL-1 family - was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.
Subject(s)
Gene Expression Regulation , Immunomodulation , Interleukin-33/genetics , Interleukin-33/metabolism , Signal Transduction , Animals , Central Nervous System/immunology , Central Nervous System/metabolism , Cytokines/metabolism , Disease Susceptibility , Humans , Immunity, Innate , Inflammation/etiology , Inflammation/metabolism , Interleukin-33/chemistry , Neoplasms/etiology , Neoplasms/metabolism , Organ Transplantation , Regeneration/genetics , Regeneration/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
Cigarette smoke and infection are the major drivers of chronic obstructive pulmonary disease. In this issue of Immunity, Kearley et al. (2015) demonstrate that smoke exposure alters the lung microenvironment leading to an interleukin-33-dependent proinflammatory disease exacerbation.
Subject(s)
Immunity, Innate/drug effects , Interleukins/immunology , Orthomyxoviridae Infections/immunology , Pulmonary Disease, Chronic Obstructive/immunology , Receptors, Interleukin/immunology , Smoke/adverse effects , Animals , Female , Humans , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33ABSTRACT
Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17(+) CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5(+) and IL-4(+) CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.
Subject(s)
Autoimmune Diseases/drug therapy , Interleukins/therapeutic use , Receptors, Interleukin/genetics , Uveitis/drug therapy , Animals , Autoimmune Diseases/immunology , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Coculture Techniques , Disease Models, Animal , Eye/immunology , Eye/pathology , Eye Proteins/immunology , Inflammation/drug therapy , Inflammation/immunology , Interferon-gamma/biosynthesis , Interleukin-1 Receptor-Like 1 Protein , Interleukin-17/biosynthesis , Interleukin-33 , Interleukin-4/biosynthesis , Interleukin-5/biosynthesis , Interleukins/biosynthesis , Interleukins/genetics , Macrophages/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/biosynthesis , Receptors, Interleukin/biosynthesis , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/metabolism , Uveitis/immunologyABSTRACT
Filarial nematodes, parasites of vertebrates, including humans, secrete immunomodulatory molecules into the host environment. We have previously demonstrated that one such molecule, the phosphorylcholine-containing glycoprotein ES-62, acts to bias the immune response toward an anti-inflammatory/Th2 phenotype that is conducive to both worm survival and host health. For example, although ES-62 initially induces macrophages to produce low levels of IL-12 and TNF-alpha, exposure to the parasite product ultimately renders the cells unable to produce these cytokines in response to classic stimulators such as LPS/IFN-gamma. We have investigated the possibility that a TLR is involved in the recognition of ES-62 by target cells, because phosphorylcholine, a common pathogen-associated molecular pattern, appears to be responsible for many of the immunomodulatory properties of ES-62. We now demonstrate that ES-62-mediated, low level IL-12 and TNF-alpha production by macrophages and dendritic cells is abrogated in MyD88 and TLR4, but not TLR2, knockout, mice implicating TLR4 in the recognition of ES-62 by these cells and MyD88 in the transduction of the resulting intracellular signals. We also show that ES-62 inhibits IL-12 induction by TLR ligands other than LPS, bacterial lipopeptide (TLR2) and CpG (TLR9), via this TLR4-dependent pathway. Surprisingly, macrophages and dendritic cells from LPS-unresponsive, TLR4-mutant C3H/HeJ mice respond normally to ES-62. This is the first report to demonstrate that modulation of cytokine responses by a pathogen product can be abrogated in cells derived from TLR4 knockout, but not C3H/HeJ mice, suggesting the existence of a novel mechanism of TLR4-mediated immunomodulation.