RESUMO
Toll-like receptors orchestrate rapid local protective innate-immune responses to invading pathogens and optimize leukocyte priming of subsequent adaptive responses. Paradoxically, systemic excess of the TLR2 ligand, bacterial lipoprotein (BLP), suppresses peripheral inflammatory responses. Here, we demonstrate that this phenomenon is regulated via the TLR2-dependent, cell-autonomous down-regulation of inflammatory chemokine receptor expression on a variety of leukocyte subsets. Remarkably, BLP mediated no effect on constitutive chemokine receptor expression. By tracking adoptively transferred wild-type and TLR2(-/-) leukocytes in vivo, we observed that BLP mediated chemokine receptor switching directed leukocytes away from inflamed sites toward secondary lymphoid organs. These data highlight a novel role for TLR ligands, such as BLP, in regulating leukocyte retention and migration away from innate immune lesions via discrete constitutive and inflammatory chemokine receptor regulation.
Assuntos
Movimento Celular/fisiologia , Inflamação/prevenção & controle , Leucócitos/fisiologia , Lipoproteínas/administração & dosagem , Receptores de Quimiocinas/metabolismo , Pele/imunologia , Receptor 2 Toll-Like/fisiologia , Animais , Células Cultivadas , Quimiocinas/metabolismo , Feminino , Citometria de Fluxo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interferon gama/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/metabolismo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (T(H)2) cells and mast cells. IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting T(H)2-type immune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding T(H)2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33 could be a new target for therapeutic intervention across a range of diseases.