RESUMEN
Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αMß2 integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in PLG, encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.
Asunto(s)
Fibrina/metabolismo , Mucosa Bucal/inmunología , Mucosa Bucal/metabolismo , Activación Neutrófila , Neutrófilos/inmunología , Periodontitis/genética , Plasminógeno/genética , Pérdida de Hueso Alveolar , Animales , Trampas Extracelulares/metabolismo , Femenino , Fibrina/química , Fibrinógeno/metabolismo , Fibrinolisina/metabolismo , Fibrinólisis , Microbioma Gastrointestinal/fisiología , Encía/inmunología , Humanos , Inmunidad Mucosa , Antígeno de Macrófago-1/metabolismo , Masculino , Ratones , Mucosa Bucal/microbiología , Periodontitis/inmunología , Plasminógeno/deficiencia , Plasminógeno/metabolismo , Polimorfismo de Nucleótido Simple , RNA-Seq , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury and perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive tissue damage, are virtually unknown. In this study, we show that fibroblasts in injured tissues undertake the clearance of collectins by using the endocytic collagen receptor uPARAP. In cellular assays, several types of collectins were endocytosed in a highly specific uPARAP-dependent process, not shared by the closely related receptor MR/CD206. When introduced into dermis or bleomycin-injured lungs of mice, collectins MBL and SP-D were endocytosed and routed for lysosomal degradation by uPARAP-positive fibroblasts. Fibroblast-specific expression of uPARAP governed endogenous SP-D levels and overall survival after lung injury. In lung tissue from idiopathic pulmonary fibrosis patients, a strong up-regulation of uPARAP was observed in fibroblasts adjacent to regions with SP-D secretion. This study demonstrates a novel immune-regulatory function of fibroblasts and identifies uPARAP as an endocytic receptor in immunity.