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1.
Allergy ; 69(6): 719-29, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24735452

RESUMO

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.


Assuntos
Regulação da Expressão Gênica , Interleucinas/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores Imunológicos/genética , Animais , Células Cultivadas , Citocinas/biossíntese , Ativação Enzimática/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , NF-kappa B/metabolismo , Ligação Proteica , Transporte Proteico , Receptores Imunológicos/metabolismo , Receptores de Interleucina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Mucosal Immunol ; 7(2): 292-303, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23820751

RESUMO

Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell (Th2) inflammation. Eotaxin-induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses. Nevertheless, the expressions of immunoreceptor tyrosine-based inhibitory motif-bearing receptors such as CMRF35-like molecule-1 (CLM-1) and their ability to govern eosinophil migration are largely unknown. We now report that CLM-1 (but not CLM-8) is highly and distinctly expressed by colonic and adipose tissue eosinophils. Furthermore, Clm1⁻/⁻ mice display elevated baseline tissue eosinophilia. CLM-1 negatively regulated eotaxin-induced eosinophil responses including eosinophil chemotaxis, actin polymerization, calcium influx, and extracellular signal-regulated kinase (ERK)-1/2, but not p38 phosphorylation. Addition of CLM-1 ligand (e.g., phosphatidylserine) rendered wild-type eosinophils hypochemotactic in vitro and blockade of CLM-1/ligand interactions rendered wild-type eosinophils hyperchemotactic in vitro and in vivo in a model of allergic airway disease. Interestingly, suppression of cellular recruitment via CLM-1 was specific to eosinophils and eotaxin, as leukotriene B4 (LTB4)- and macrophage inflammatory protein-1α (MIP-1α)-induced eosinophil and neutrophil migration were not negatively regulated by CLM-1. Finally, peripheral blood eosinophils obtained from allergic rhinitis patients displayed elevated CLM-1/CD300f levels. These data highlight CLM-1 as a novel regulator of eosinophil homeostasis and demonstrate that eosinophil accumulation is constantly governed by CLM-1, which negatively regulates eotaxin-induced eosinophil responses.


Assuntos
Quimiotaxia/fisiologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Homeostase , Receptores Imunológicos/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Quimiocina CCL11/farmacologia , Quimiocina CCL24/farmacologia , Quimiocina CCL3/farmacologia , Quimiotaxia/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Eosinófilos/efeitos dos fármacos , Humanos , Leucotrieno B4/farmacologia , Ligantes , Camundongos , Camundongos Knockout , Ligação Proteica , Receptores Imunológicos/genética , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo
3.
Clin Exp Allergy ; 40(5): 700-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20447082

RESUMO

An intricate network of activation and inhibitory signals tightly regulates immune responses. To date, multiple activation receptors have been described. These include receptors that mediate cellular functions such as adhesion, chemotaxis, cytokine signalling, mediator release, survival and phagocytosis. In contrast to these activation pathways, an opposing and suppressive receptor system has evolved. These receptors can override the signals elicited by the activation pathways and are broadly termed inhibitory receptors. Inhibitory receptors share unique intracellular signalling motifs and have key roles in various cellular and pathological conditions. Therefore, such receptors are potential targets for future therapeutics. In this review, we will discuss the structure and function of inhibitory receptors. In particular, we will focus on the expression and function of inhibitory receptors on mast cells and eosinophils and illustrate strategies for their inhibition in the settings of allergic inflammation.


Assuntos
Hipersensibilidade/imunologia , Inflamação/imunologia , Receptores KIR/imunologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Humanos , Hipersensibilidade/tratamento farmacológico , Mastócitos/imunologia , Mastócitos/metabolismo , Domínios e Motivos de Interação entre Proteínas/imunologia , Receptores KIR/antagonistas & inibidores , Receptores KIR/química , Transdução de Sinais
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