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J Immunol ; 198(1): 318-334, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27852744

RESUMO

Candida albicans infection produces elongated hyphae resistant to phagocytic clearance compelling alternative neutrophil effector mechanisms to destroy these physically large microbial structures. Additionally, all tissue-based neutrophilic responses to fungal infections necessitate contact with the extracellular matrix (ECM). Neutrophils undergo a rapid, ECM-dependent mechanism of homotypic aggregation and NETosis in response to C. albicans mediated by the ß2 integrin, complement receptor 3 (CR3, CD11b/CD18, αMß2). Neither homotypic aggregation nor NETosis occurs when human neutrophils are exposed either to immobilized fungal ß-glucan or to C. albicans hyphae without ECM. The current study provides a mechanistic basis to explain how matrix controls the antifungal effector functions of neutrophils under conditions that preclude phagocytosis. We show that CR3 ligation initiates a complex mechanism of integrin cross-talk resulting in differential regulation of the ß1 integrins VLA3 (α3ß1) and VLA5 (α5ß1). These ß1 integrins control distinct antifungal effector functions in response to either fungal ß-glucan or C. albicans hyphae and fibronectin, with VLA3 inducing homotypic aggregation and VLA5 regulating NETosis. These integrin-dependent effector functions are controlled temporally whereby VLA5 and CR3 induce rapid, focal NETosis early after binding fibronectin and ß-glucan. Within minutes, CR3 undergoes inside-out auto-activation that drives the downregulation of VLA5 and the upregulation of VLA3 to support neutrophil swarming and aggregation. Forcing VLA5 to remain in the activated state permits NETosis but prevents homotypic aggregation. Therefore, CR3 serves as a master regulator during the antifungal neutrophil response, controlling the affinity states of two different ß1 integrins, which in turn elicit distinct effector functions.


Assuntos
Matriz Extracelular/imunologia , Armadilhas Extracelulares/imunologia , Integrina alfa3beta1/imunologia , Neutrófilos/imunologia , beta-Glucanas/imunologia , Candida albicans/imunologia , Separação Celular , Transferência Ressonante de Energia de Fluorescência , Proteínas Fúngicas/imunologia , Humanos , Antígeno de Macrófago 1/imunologia , Microscopia Eletrônica de Varredura , Receptor Cross-Talk/imunologia
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