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Previous studies have shown that complement activation on renal tubular cells is involved in the induction of interstitial fibrosis and cellular injury. Evidence suggests that the tubular cell damage is initiated by the alternative pathway (AP) of complement with properdin having an instrumental role. Properdin is a positive regulator of the AP, which can bind necrotic cells as well as viable proximal tubular epithelial cells (PTECs), inducing complement activation. Various studies have indicated that in the circulation there is an unidentified inhibitor of properdin. We investigated the ability of C-reactive protein (CRP), both in its monomeric (mCRP) and pentameric (pCRP) form, to inhibit AP activation and injury in vitro on renal tubular cells by fluorescent microscopy, ELISA, and flow cytometry. We demonstrated that preincubation of properdin with normal human serum inhibits properdin binding to viable PTECs. We identified mCRP as a factor able to bind to properdin in solution, thereby inhibiting its binding to PTECs. In contrast, pCRP exhibited no such binding and inhibitory effect. Furthermore, mCRP was able to inhibit properdin-directed C3 and C5b-9 deposition on viable PTECs. The inhibitory ability of mCRP was not unique for viable cells but also demonstrated for binding to necrotic Jurkat cells, a target for properdin binding and complement activation. In summary, mCRP is an inhibitor of properdin in both binding to necrotic cells and viable renal cells, regulating complement activation on the cell surface. We propose that mCRP limits amplification of tissue injury by controlling properdin-directed complement activation by damaged tissue and cells., (Copyright © 2016 the American Physiological Society.)

Fibroblasts reside within the renal interstitium in close proximity to neighbouring dendritic cells (DCs). It is likely that these cells have a central role in the maintenance and function of resident and infiltrating renal DCs, though studies to confirm this have been lacking. We investigated whether renal fibroblasts influence human DC generation and function. We found that co-culture with renal fibroblasts led to the generation of monocyte-derived dendritic cells (Fibro-DCs), with significantly reduced CD80, CD83 and CD86 but elevated B7H1 and B7DC expression. In addition, these Fibro-DCs displayed a reduced capacity to produce interleukin (IL)-12p40 and IL-12p70 but maintained normal levels of IL-23 and IL-27. Furthermore, IL-10 production was elevated, which together resulted in a regulatory DC population with a reduced capacity to stimulate allogenic T-cell proliferation and interferon γ production, while preserving IL-17A. Supernatant transfer experiments suggested that a soluble mediator from the fibroblasts was sufficient to inhibit the immunogenic capability of DCs. Further experiments demonstrated that IL-6 was at least partially responsible for the modulating effect of renal fibroblasts on DC generation and subsequent function. In summary, renal fibroblasts may have a crucial decisive role in regulating local DC immune responses in vivo. Better understanding of this cell population and their mechanisms of action may have therapeutic relevance in many immune-driven renal diseases.