The acute-phase protein C-reactive protein (CRP) recruits C1q to the surface of damaged cells and thereby initiates complement activation. However, CRP also recruits complement inhibitors, such as C4b-binding protein (C4bp) and factor H, which both block complement progression at the level of C3 and inhibits inflammation. To define how CRP modulates the classic complement pathway, we studied the interaction of CRP with the classic pathway inhibitor C4bp. Monomeric CRP (mCRP), but not pentameric CRP (pCRP), binds C4bp and enhances degradation of C4b and C3b. Both C1q, the initiator, and C4bp, the inhibitor of the classic pathway, compete for mCRP binding, and this competition adjusts the local balance of activation and inhibition. After attachment of pCRP to the surface of necrotic rat myocytes, generation of mCRP was demonstrated over a period of 18 h. Similarly, a biological role for mCRP, C1q, and C4bp in the disease setting of acute myocardial infarction was revealed. In this inflamed tissue, mCRP, pCRP, C4bp, C1q, and C4d were detected in acetone-fixed and in unfixed tissue. Protein levels were enhanced 6 h to 5 d after infarction. Thus, mCRP bound to damaged cardiomyocytes recruits C1q to activate and also C4bp to control the classic complement pathway.

Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte-derived and mouse bone marrow-derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro-inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17-instructive cytokines upon pro-inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17-driven psoriasis-like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity-mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17-mediated inflammation such as psoriasis in response to an inflammatory danger signal.Keywords: Dendritic cells r Diet r Free fatty acids r Inflammation r Metabolism r TH1 r TH17 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHuman and mouse studies demonstrate that immune responses are dysregulated in obesity. In particular, obesity in mice is associated with increased inflammation and/or its delayed resolution Correspondence: Dr. Anja Saalbach e-mail: Anja. Saalbach@medizin.uni-leipzig.de in models of acute pancreatitis, arthritis, and neutrophil-mediated peritonitis [1][2][3][4]. Kanemaru et al. described a worsening of psoriasis from dermatitis in mice by upregulating IL-17A, IL-22, and Reg3c in skin [5]. Likewise human psoriasis, a chronic TH1/TH17-driven inflammatory skin disease, shows a significant positive * These authors contributed equally to this work. Eur. J. Immunol. 2016Immunol. . 46: 2043Immunol. -2053 correlation between body mass index (BMI) and the onset and severity of the disease as well as a weaker response to treatment [6,7]. Obesity is associated with low-grade chronic inflammation reflected by increased levels of acute-phase proteins and pro-inflammatory mediators as well as by a pro-inflammatory state of circulating mononuclear cells in obese compared to lean subjects [3,8]. Enlarged adipocytes change their secretion pattern and release more pro-inflammatory mediators such as TNF-α and MCP-1, while the release of anti-inflammatory mediators such as adiponectin is reduced [9][10][11]. Thus, white adipose tissue could link metabolism and inflammation [12]. Moreover, in obesity, visceral adipose tissues as well as subcutaneous fat depots enlarge and adipocyte production of free fatty acids (FFAs), mainly palmitic acid (PA)...

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