Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel <i>Il-33–LacZ</i> Gene Trap Reporter Strain

Pichery, Mélanie; Mirey, Emilie; Mercier, Pascale; Lefrançais, Emma; Dujardin, Arnaud; Ortéga, Nathalie; Girard, Jean-Philippe

doi:10.4049/jimmunol.1101977

Cited by 429 publications

(423 citation statements)

References 43 publications

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“…Source of IL-33 in GAT has not been clarified yet. It is reported that IL-33 protein is expressed and induced by stimuli in limited tissue [31]. Our data show il33 mRNA is abundant in lung but few in GAT.…”

supporting

confidence: 56%

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

et al. 2015

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Eosinophils are multifunctional leukocytes involved in allergic reactions as well as adipose tissue regulation. IL-5 is required for eosinophil survival; however, the in vivo mechanisms of eosinophil regulation are not fully understood. A tg mouse model with il5 promoter-driven EGFP expression was established for detecting the IL-5-producing cells in vivo. Il5-egfp tg mice expressed high levels of EGFP in gonadal adipose tissue (GAT) cells. EGFP + cells in GAT were mainly group 2 innate lymphoid cells (ILCs). IL-33 preferentially expanded EGFP + cells and eosinophils in GAT in vivo. EGFP + ILCs were found to upregulate prg2 mRNA expression in GAT eosinophils. These results demonstrate that ILCs activate eosinophils in GAT. The blockage of IL-33Rα, on the other hand, did not impair EGFP + ILC numbers but did impair eosinophil numbers in vivo. GAT eosinophils expressed IL-33Rα and IL-33 expanded eosinophil numbers in CD90 + cell-depleted mice. IL-33 was further observed to induce the expression of retnla and epx mRNA in eosinophils. These findings demonstrate that IL-33 directly activates eosinophils in GAT, and together with our other findings described above, our findings show that IL-33 has dual pathways via which it activates eosinophils in vivo: a direct activation pathway and a group 2 ILCmediated pathway. Keywords: Eosinophils r IL-33 r Innate lymphoid cells r IL-5Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionEosinophils are multifunctional leukocytes involved in the elimination of parasites and the initiation of allergic reactions [1]. Eosinophils secrete major basic protein (MBP, prg2), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin, which damage parasites, and in some cases, damage healthy tissues as well [1]. Eosinophils also play critical roles in metabolic homeostasis relating to obesity [2]. GATA-1 is critical to eosinophil development, and dblGATA mice, in which the GATA binding sites in the Gata1 promoter are mutated, are prone to obesity when fed a high-fat diet [2,3]. Eosinophils are located Correspondence: Associate Prof. Masaaki Hashiguchi e-mail: mhashi@dokkyomed.ac.jp in visceral adipose tissue, and the loss of eosinophils leads to a decrease in alternatively activated macrophage (AAM) accumulation [2]. AAMs in gonadal adipose tissue (GAT) are maintained by . The activation of eosinophils critically depends on IL-5: studies using il5-tg mice or il5-deficient mice and anti-IL-5 Ab have demonstrated that the expansion of eosinophils is largely regulated by . Il5-deficient mice show higher body weight and visceral adipose weight in response to a highfat diet [2]. Deficiency of il5 or eosinophils impairs glucose consumption and promotes obesity [2] and adipose tissue metabolism is thus regulated by eosinophils through the activation of AAMs [2,3,9].Innate lymphoid cells (ILCs) play a protective role against foreign pathogens [10]. ILCs are classified into at least three groups, de...

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supporting

confidence: 56%

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

et al. 2015

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“…Although epithelial barrier tissues and endothelial cells are generally known to express IL-33 (36,37), some immune cells, such as macrophages and dendritic cells, can produce IL-33 under certain inflammatory conditions (38,39). However, the level of IL-33 produced by hematopoietic cells is much less than that from epithelial cells (39,40), and tissuederived IL-33 is critical for induction of allergic inflammation (41).…”

Section: Discussionmentioning

confidence: 99%

Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa

Kim

Chang

et al. 2016

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

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Commensal microbiota are well known to play an important role in antiviral immunity by providing immune inductive signals; however, the consequence of dysbiosis on antiviral immunity remains unclear. We demonstrate that dysbiosis caused by oral antibiotic treatment directly impairs antiviral immunity following viral infection of the vaginal mucosa. Antibiotic-treated mice succumbed to mucosal herpes simplex virus type 2 infection more rapidly than water-fed mice, and also showed delayed viral clearance at the site of infection. However, innate immune responses, including type I IFN and proinflammatory cytokine production at infection sites, as well as induction of virusspecific CD4 and CD8 T-cell responses in draining lymph nodes, were not impaired in antibiotic-treated mice. By screening the factors controlling antiviral immunity, we found that IL-33, an alarmin released in response to tissue damage, was secreted from vaginal epithelium after the depletion of commensal microbiota. This cytokine suppresses local antiviral immunity by blocking the migration of effector T cells to the vaginal tissue, thereby inhibiting the production of IFN-γ, a critical cytokine for antiviral defense, at local infection sites. These findings provide insight into the mechanisms of homeostasis maintained by commensal bacteria, and reveal a deleterious consequence of dysbiosis in antiviral immune defense.commensal microbiota | dysbiosis | IL-33 | herpes simplex virus type 2 | genital tract

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“…Therefore, although mast cell proteases are differentially expressed in different mast cell subsets (42), all types of mast cells, including mucosal and connective tissue mast cells, may be able to generate highly active mature forms of IL-33. Mast cells are located close to IL-33-producing cells in tissues (33,34,39), and they interact very closely with ILC2s in vivo (26). Mast cells and the proteases they secrete are thus likely to play an important role in the activation of the IL-33 alarm signal during inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore investigated the possibility that other cell types may be involved in this process. Mast cells, which are widely recognized for their roles as effector cells in allergic disorders, were good candidates because they interact directly with ILC2s in vivo (26) and they are strategically positioned close to vessel walls and epithelial surfaces exposed to the environment (39), the major sites of IL-33 expression (33,34). We now demonstrate that activated human mast cells and purified mast cell proteases, tryptase and chymase, generate mature forms of IL-33 (IL-33 , IL-33 , and IL-33 109-270 ), which are ∼30-fold more potent than full-length IL-33 for activation of ILC2s ex vivo.…”

mentioning

confidence: 99%

“…Full-length human IL-33 is a 270 amino acid protein localized in the nucleus of endothelial and epithelial cells in blood vessels and epithelial barrier tissues (1,2,33,34), which associates with chromatin (2) and histones H2A-H2B, through a short chromatinbinding motif located in its N-terminal part (amino acids 40-58) (35). IL-33 can be released in the extracellular space upon cellular damage or necrotic cell death (36,37), and it was thus proposed to function as an alarmin (alarm signal or endogenous danger signal), which alerts the immune system to tissue injury following trauma or infection (33,36,37).…”

mentioning

confidence: 99%

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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.

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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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Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel Il-33–LacZ Gene Trap Reporter Strain

Cited by 429 publications

References 43 publications

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa

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

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