C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response

Abstract

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 Ca2+-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 β. 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.

C‐reactive protein impairs human CD14+ monocyte‐derived dendritic cell differentiation, maturation and function

“…Additionally, CRP has been shown to be protective against bacterial infections [15], a variety of inflammatory conditions and various mediators of inflammation [16]. Gershov et al demonstrated that CRP may interact with apoptotic cells and promote noninflammatory clearance of apoptotic cells [17]. Recent studies on CRP have raised more interest in the regulatory role of CRP in inflammation and autoimmunity [18].…”

Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins

“…C1q binds avidly in this cleft, thereby inducing complement activation via formation of the classical C3 convertase, which in turn leads to decoration of the ligand surface with opsonizing complement fragments [8,61]. The ability to induce the complement cascade has been reported to be a unique feature of the pentameric CRP form [21,62] and the activation is progressively increased by the presence of apoptotic cells with immobilized cell surfaces [63]. However, a recent report by Ji et al indicates that mCRP may also have a regulartory role of the classical complement pathway, depending on whether the interaction with C1q appears in fluid-phase or surface-bound state [64].…”

“…This may be of etiopathogenic importance concerning both immunoregulation and induction of autoimmunity [6,73]. Regarding the capacity of CRP to bind nuclear antigens/apoptotic cells and to interact with FcRs, it has been proposed that the modest CRP response in SLE contributes to the deficient handling of apoptotic material, thereby increasing the risk of abnormal immunization to autoantigens [63].…”

“…Anti-CRP may also have other pathogenic implications, for instance by reacting with surfacebound CRP on cells and tissue surfaces. Hypothetically, mCRP exposed on surfaces of apoptotic bodies, for instance in the renal glomeruli [158,159], could constitute a target for circulating anti-CRP antibodies in situ, which may subsequently initiate or amplify inflammation in the target organs [63,160]. In analogy, both anti-C1q antibodies and presence of C1q-containing ICs in glomerulus are needed to induce renal exacerbation in lupus-prone mouse models [161] (Figure 5).…”

Deciphering complement mechanisms: The contributions of structural biology

“…Superimposed on this differential affinity for specific GAGs displayed by the two allotypic variants, there are differences in their affinity for C-reactive protein (Laine et al, 2007;Sjoberg et al, 2007;Herbert et al, 2007). In this context, it is noteworthy that factor H might be recruited to apoptotic cells through its affinity for CRP, whereupon it reduces inflammatory complement stimulation (Gershov et al, 2000). Flexibility between adjacent CCPs would allow an RCA to change shape during the process of performing its biological role.…”