RESUMEN
C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca(2+)-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor beta. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.
Asunto(s)
Apoptosis/inmunología , Autoinmunidad/inmunología , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , Vía Clásica del Complemento/inmunología , Apoptosis/efectos de los fármacos , Calcio/farmacología , Complemento C1q/inmunología , Complemento C1q/metabolismo , Complemento C3b/inmunología , Complemento C3b/metabolismo , Factor H de Complemento/inmunología , Factor H de Complemento/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/efectos de los fármacos , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Vía Clásica del Complemento/efectos de los fármacos , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inflamación/inmunología , Células Jurkat , Macrófagos/inmunología , Macrófagos/metabolismo , Necrosis , Proteínas Opsoninas/inmunología , Proteínas Opsoninas/farmacología , Fagocitosis , Unión Proteica/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.