Anti-C1q Autoantibodies from Systemic Lupus Erythematosus Patients Induce a Proinflammatory Phenotype in Macrophages

Abstract

Anti-C1q autoantibodies (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE) and correlate with the occurrence of proliferative lupus nephritis. A previous study of anti-C1q in experimental lupus nephritis demonstrated an important role for FcγRs in the pathogenesis of lupus nephritis, suggesting a direct effect on phagocytes. Therefore, we developed an in vitro model to study the effect of SLE patient–derived anti-C1q bound to immobilized C1q (imC1q) on human monocyte-derived macrophages (HMDMs) obtained from healthy donors and SLE patients. HMDMs were investigated by analyzing the cell morphology, LPS-induced cytokine profile, surface marker expression, and phagocytosis rate of apoptotic Jurkat cells. Morphologically, bound anti-C1q induced cell aggregations of HMDMs compared with imC1q or IgG alone. In addition, anti-C1q reversed the effect of imC1q alone, shifting the LPS-induced cytokine release toward a proinflammatory response. FcγR-blocking experiments revealed that the secretion of proinflammatory cytokines was mediated via FcγRII. The anti-C1q–induced inflammatory cytokine profile was accompanied by a downregulation of CD163 and an upregulation of LPS-induced CD80, CD274, and MHC class II. Finally, HMDMs primed on bound anti-C1q versus imC1q alone displayed a significantly lower phagocytosis rate of early and late apoptotic cells accompanied by a reduced Mer tyrosine kinase expression. Interestingly, anti-C1q–dependent secretion of proinflammatory cytokines was similar in SLE patient–derived cells, with the exception that IL-10 was slightly increased. In conclusion, anti-C1q induced a proinflammatory phenotype in HMDMs reversing the effects of imC1q alone. This effect might exacerbate underlying pathogenic mechanisms in lupus nephritis.

Binding of von Willebrand Factor to Complement C1q Decreases the Phagocytosis of Cholesterol Crystals and Subsequent IL-1 Secretion in Macrophages

“…In this context, C1q has been shown to elicit upregulated expression of MerTK receptor, which is involved in the process of dead cell removal, termed efferocytosis (33). Moreover, it has been described that stimulation of macrophages with C1q leads to a polarization of these cells toward an anti-inflammatory state (34). Therefore, we aimed to investigate the phenotype of HMDMs in our in vitro model.…”

Opsonization of Early Apoptotic Cells by IgG from Lupus Nephritis Amplifies Activation of Early Complement Components and Promotes Inflammatory Phagocytosis

“…Our results indicated that opsonization of IgG from lupus promoted rapid clearance of early apoptotic cells, but it changed early apoptotic cells from anti-inflammatory to proinflammatory properties, which indicated a contributor in the pathogenesis of lupus. Sophia et al demonstrated that anti-C1q from lupus induced a proinflammatory phenotype in macrophages reversing the effects of C1q alone [26]. In a recent research, the Ro 60 autoantigen could bind endogenous retroelements and regulate inflammatory gene expression [27], which might provide a direction to investigate the underling mechanisms of proinflammatory property of patient IgG.…”

Sirtuin 1 (Sirt1) Overexpression in BaF3 Cells Contributes to Cell Proliferation Promotion, Apoptosis Resistance and Pro-Inflammatory Cytokine Production

“…Pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, play pivotal roles in inflammation and the maturation of B cells, and have been proven to be closely related to the pathophysiology of SLE [25,26]. IL-6 is produced by TNF-α and supposedly upregulates the number of inflammatory cells [27].…”