C-Reactive Protein-Mediated Suppression of Nephrotoxic Nephritis: Role of Macrophages, Complement, and Fcγ Receptors

Abstract

C-reactive protein (CRP) is a member of the pentraxin family of proteins and an acute phase reactant. CRP modulates the response to inflammatory stimuli including LPS and C5a. We recently demonstrated that CRP prevents and reverses proteinuria in accelerated nephrotoxic nephritis (NTN). NTN is a model of active inflammatory immune complex-mediated nephritis induced by injection of antiglomerular basement membrane. CRP treatment prevented the induction of NTN in C57BL/6 (B6) mice, increased survival, and reversed ongoing nephritis. Protection was associated with a decrease in IL-1β and chemokines in the kidney and peritoneal cells as measured by quantitative RT-PCR. However, IL-10−/− mice were not protected by CRP either when given before disease onset or when disease activity was maximal. FcγRI−/− mice developed NTN, but were only transiently protected by CRP treatment. This transient protection was abrogated by cobra venom factor depletion of complement from FcγRI−/− mice. However, complement depletion did not prevent CRP-mediated protection in B6 mice, and CRP was protective in C3−/− mice. The role of macrophages in the protection provided by CRP was tested by treating B6 mice with liposomes containing clodronate. Clodronate-containing liposomes deplete mice of splenic and hepatic macrophages for 5–7 days. Pretreatment of NTN mice with clodronate but not control liposomes completely prevented CRP-mediated protection. These studies suggest that CRP mediates protection from NTN through the induction of IL-10 and that macrophages are required. In addition, FcγRI plays an important role but is not the sole mediator of CRP-mediated protection.

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

“…Further experiments are clearly needed to address this point in more detail, such as by using recently established IL-17 fate reporter mice. 30 Furthermore, we reemphasize that Foxp3 YFP-Cre x Il10 flox/flox mice as well as recipient mice in transfer experiments still harbor a large proportion of IL-10 + immune-regulatory cells other than Tregs, as shown by own (Figure 3, A-D [31][32][33][34][35] Further studies using the FIR x tiger mice as well as the Cre/loxP system are intended to study the potential role of these cells in more detail.…”

Acute Phase Proteins: Structure and Function Relationship

“…A single injection of CRP both prevents and reverses accelerated nephrotoxic nephritis (NTN) in C57BL/6 mice (Rodriguez et al, 2005) indicating that CRPinduced suppression of immune complex-mediated inflammation is not limited to autoimmune nephritis. Protection from NTN by CRP was associated with a decrease in inflammatory and pathologic changes in glomeruli and a marked reduction in renal expression of IL-1 and other macrophage chemoattractants (Rodriguez et al, 2007).…”

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

“…CRP and SAP have been shown to bind and activate Fcγ receptors (FcγR) on monocytes and macrophages (1,(3)(4)(5)(6). In addition, CRP suppressed immune complex-mediated nephrotoxic nephritis in a mouse model (7). Despite their distinct folds, both antibody and pentraxins bind FcγR in a 1:1 stoichiometry, obligating pathogen opsonization or immune complex formation as the mechanism for receptor clustering and activation (6,8,9).…”