title: Interleukin-33 requires CMRF35-like molecule-1 expression for induction of myeloid cell activation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 Clm1(-/-) cells and mice.
  
  
  RESULTS
  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 (in vitro and in vivo). Clm1(-/-) 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 Clm1(-/-) 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 Clm1(-/-) mice, eosinophil accumulation was similar in wt and Clm1(-/-) mice, due to hyperchemotactic responses of Clm1(-/-) eosinophils.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Shik
authors.forename: I
authors.initials: I
authors.lastname: Moshkovits
authors.forename: D
authors.initials: D
authors.lastname: Karo-Atar
authors.forename: H
authors.initials: H
authors.lastname: Reichman
authors.forename: A
authors.initials: A
authors.lastname: Munitz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C482560:CLM-1 protein, mouse; D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CMRF-35-like molecule 1; IL-33; eosinophils