Interleukin‐33 requires CMRF35‐like molecule‐1 expression for induction of myeloid cell activation. Issue 6 (15th April 2014)

• Record Type: Journal Article
• Authors: Shik, D.; Moshkovits, I.; Karo‐Atar, D.; Reichman, H.; Munitz, A.
• Is Part Of: Allergy. Volume 69:Issue 6(2014:Jun.)
• Page Start: 719
• Page End: 729
• Publication Date: 2014-04-15
• Subjects: Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.12388
• Languages: English
• ISSNs: 0105-4538

Abstract

<abstract abstract-type="main" id="all12388-abs-0001"> <title>Abstract</title> <sec id="all12388-sec-0001" sec-type="section"> <title>Background</title> <p>IL‐33 is a potent activator of various cells involved in allergic inflammation, including eosinophils and mast cells. Despite its critical role in Th2 disease settings, endogenous molecular mechanisms that may regulate IL‐33‐induced responses remain to be defined. We have recently shown that eosinophils express CMRF35‐like molecule (CLM)‐1. Yet, the role of CLM‐1 in regulating eosinophil functions is still elusive.</p> </sec> <sec id="all12388-sec-0002" sec-type="section"> <title>Methods</title> <p>CLM‐1 and CLM‐8 expression and cellular localization were assessed in murine bone marrow‐derived and/or peritoneal cells at baseline and following IL‐33 stimulation (flow cytometry, western blot). IL‐33‐induced mediator release and signaling were assessed in wild‐type (wt) and <italic>Clm1</italic><sup><italic>−/−</italic></sup> cells and mice.</p> </sec> <sec id="all12388-sec-0003" sec-type="section"> <title>Results</title> <p>BM‐derived eosinophils express high levels of glycosylated CLM‐1. IL‐33 induced a rapid, specific, concentration‐ and time‐dependent upregulation of CLM‐1 in eosinophils (<italic>in vitro</italic> and <italic>in vivo</italic>)<italic>. Clm1</italic><sup><italic>−/−</italic></sup> eosinophils secreted less IL‐33‐induced mediators than wt eosinophils. CLM‐1 co‐localized to ST2 following IL‐33 stimulation and was required for IL‐33‐induced NFκB and p38 phosphorylation. Th2 cytokine (e.g., IL‐5, IL‐13) and chemokine (e.g., eotaxins, CCL2) secretion was markedly attenuated in IL‐33‐treated <italic>Clm1</italic><sup><italic>−/−</italic></sup> mice. Subsequently, IL‐33‐challenged mice displayed reduced infiltration of mast cells, macrophages, neutrophils, and B cells. Despite the markedly impaired IL‐33‐induced eotaxin expression in <italic>Clm1</italic><sup><italic>−/−</italic></sup> mice, eosinophil accumulation was similar in wt and <italic>Clm1</italic><sup><italic>−/−</italic></sup> mice, due to hyperchemotactic responses of <italic>Clm1</italic><sup><italic>−/−</italic></sup> eosinophils.</p> </sec> <sec id="all12388-sec-0004" sec-type="section"> <title>Conclusions</title> <p>CLM‐1 is a novel regulator of IL‐33‐induced eosinophil activation. These data contribute to the understanding of endogenous molecular mechanisms regulating IL‐33‐induced responses and may ultimately lead to receptor‐based tools for future therapeutic intervention in IL‐33‐associated diseases.</p> </sec> </abstract>