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Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions¹

Rahul Purwar^2,*, Miriam Wittmann^*, Jörg Zwirner, Martin Oppermann, Michael Kracht, Oliver Dittrich-Breiholz, Ralf Gutzmer^* and Thomas Werfel^*

^* Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany; Department of Immunology, Georg-August-University, Göttingen, Germany; and Institute of Pharmacology, Hannover Medical University, Hannover, Germany

The complement fragment-3a (C3a) acts via a G protein-coupled C3aR and is of importance in allergic and inflammatory diseases. Recent studies suggest the presence of complement proteins in the epidermal compartment and synthesis of some of these proteins (C3, factor B, and factor H) by human primary keratinocytes (KCs) during inflammation. However, expression of C3aR and its role in human KCs is not elucidated thus far. In this study, we demonstrate the expression of C3aR on KCs as detected by quantitative real-time RT-PCR and flow cytometry. IFN- and IFN- strongly up-regulated the surface expression of C3aR on KCs among all other cytokines tested. After up-regulation of C3aR by IFN- and IFN-, we observed the induction of five genes (CCL2, CCL5, CXCL8, CXCL10, and C3) after stimulation of KCs with C3a in microarray analysis. We confirmed the induction of C3 and CCL2 at RNA and protein levels. Furthermore, incubation of C3 with skin mast cells tryptase resulted in the generation of C3 fragments with C3a activity. In conclusion, our data illustrate that epidermal KCs express functional C3aR. The increases of C3 and CCL2 synthesis by C3a and C3 activation by skin mast cell tryptase delineates a novel amplification loop of complement activation and inflammatory responses that may influence the pathogenesis of allergic/inflammatory skin diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Deutsche Forschungsgemeinschaft Grant SFB 566, A6, and Deutsche Forschungsgemeinschaft Grant Gu 434/4-I.

² Address correspondence and reprint requests to Dr. Rahul Purwar, Department of Dermatology and Allergology, Hannover Medical University, Ricklinger Strasse 05, Hannover D-30449, Germany. E-mail address: purwar.rahul{at}mh-hannover.de

³ Abbreviations used in this paper: C3a, complement fragment-3a; DC, dendritic cell; KC, keratinocyte; AD, atopic dermatitis; RT, room temperature; qRT-PCR, quantitative real-time RT-PCR; LTB₄, leukotriene B₄.

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