Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity

Barlow, Jillian L.; Bellosi, Agustin; Hardman, Clare S.; Drynan, Lesley; Wong, See Heng; Cruickshank, James; McKenzie, Andrew N. J.

doi:10.1016/j.jaci.2011.09.041

Cited by 431 publications

(430 citation statements)

References 31 publications

(27 reference statements)

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“…27 Airway goblet cell formation can be efficiently induced by airway delivery of IL33, which leads to macrophage and lymphocyte production of IL13. 14,[30][31][32][33] To test if autophagy plays a role in cytokine-induced inflammation in vivo, we compared the response of wild-type (WT) and Atg16l1 hypomorphic (HM) mice (Atg16l1 HM/HM ) 27 following intranasal administration of IL33. Airways of control mice (na€ ıve vehicle treated) contained few if any detectable goblet cells.…”

Section: Il33-induced Airway Goblet Cell Hypertrophy In Atg16l1-deficmentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

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Section: Il33-induced Airway Goblet Cell Hypertrophy In Atg16l1-deficmentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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“…These cells control eosinophil homeostasis in blood and adipose tissue (18,19) and produce extremely high amounts of the type-2 cytokines IL-5 and IL-13 in response to IL-33 (14)(15)(16). ILC2s also play important roles in allergic airway inflammation (20)(21)(22)(23)(24), atopic skin disease (25)(26)(27)(28), helminth infection in the intestine (11,12,(14)(15)(16), and influenza virus infection in the lungs (29,30).…”

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confidence: 99%

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Lefrançais

Duval

Mirey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

316

310

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Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33 95-270 , IL-33 107-270 , and IL-33 109-270 , were 30-fold more potent than full-length human IL-33 1-270 for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.cytokine | IL-33 | allergic inflammation | mast cell protease | innate lymphoid cells

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“…ILC2 are potently activated by the innate cytokines IL-33 and IL-25, and a vital role for these cells as a source of IL-13, required for the expulsion of intestinal helminths, has been determined (7,8,10). Furthermore, several groups reported an important role for ILC2 in allergy and airway inflammation and homeostasis (11)(12)(13)(14). We recently showed that transfer of ST2-expressing ILC2 into ST2-deficient mice was sufficient to mediate airway inflammation, mucus deposition, and cytokine production induced by administration of intranasal (i.n.)…”

mentioning

confidence: 99%

Type 2 Innate Lymphoid Cells Drive CD4+ Th2 Cell Responses

Mirchandani

Besnard

Yip

et al. 2014

The Journal of Immunology

276

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CD4+ T cells have long been grouped into distinct helper subsets on the basis of their cytokine-secretion profile. In recent years, several subsets of innate lymphoid cell have been described as key producers of these same Th-associated cytokines. However, the functional relationship between Th cells and innate lymphoid cells (ILCs) remains unclear. We show in this study that lineage-negative ST2+ICOS+CD45+ type 2 ILCs and CD4+ T cells can potently stimulate each other’s function via distinct mechanisms. CD4+ T cell provision of IL-2 stimulates type 2 cytokine production by type 2 ILCs. By contrast, type 2 ILCs modulate naive T cell activation in a cell contact–dependent manner, favoring Th2 while suppressing Th1 differentiation. Furthermore, a proportion of type 2 ILCs express MHC class II and can present peptide Ag in vitro. Importantly, cotransfer experiments show that type 2 ILCs also can boost CD4+ T cell responses to Ag in vivo.

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Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity

Cited by 431 publications

References 31 publications

IL13 activates autophagy to regulate secretion in airway epithelial cells

IL13 activates autophagy to regulate secretion in airway epithelial cells

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Type 2 Innate Lymphoid Cells Drive CD4+ Th2 Cell Responses

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