Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Abstract

In immune complex (IC) diseases, FcR are essential molecules facilitating polymorphonuclear cell (PMN) recruitment and effector functions at the IC site. Although FcR-dependent initial tethering and FcR/integrin-dependent PMN accumulation were postulated, their underlying mechanisms remain unclear. We here addressed potential mechanisms involved in PMN recruitment in acute IC glomerulonephritis (nephrotoxic nephritis). Since some renal cells may be recruited from bone marrow (BM) lineages, reconstitution studies with BM chimeras and PMN transfer between wild-type (WT) and FcR-deficient mice (γ−/−) were performed. Severe glomerular damage was induced in WT and Wγ chimeras (BM from WT to irradiated γ−/−), while it was absent in γ−/− and γW chimeras (γ−/− BM to WT). Moreover, WT PMN transfer, but not γ−/− PMN, reconstituted the disease in γ−/−, indicating that FcR on resident cells is not a prerequisite for PMN recruitment in this disease. Surprisingly, transferred WT PMN were recruited coincidentally with NF-κB activation and TNF-α overexpression even in glomeruli with preformed IC (nephrotoxic Ab administered 3 days previously), suggesting that PMN can initially be recruited via its own FcR without previous chemoattractant release. Furthermore, H2O2 inhibition by catalase attenuated the acute WT PMN recruitment and the induction of NF-κB and TNF-α much more than integrin (CD18) blockade, indicating a role for the respiratory burst before integrin-dependent accumulation. In coculture experiments with IC-stimulated PMN and glomeruli, PMN caused acute glomerular TNF-α expression predominantly via FcR-mediated H2O2 production. In conclusion, glomerular IC, even preformed, can cause PMN recruitment and injury through PMN FcR-mediated respiratory burst during initial PMN tethering to IC.

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

“…39 The multicomponent phagocyte-like NADPH oxidase is a major source of superoxide production in many nonphagocytic cells, including mesangial and tubular cells, and its activity can be upregulated by hyperglycemia, hyperlipidemia, and immune stimulation. [40][41][42][43] We believe this study is the first to demonstrate that FcgR engagement in mesangial cells activates assembly of NADPH oxidase subunits (p47 phox and p67 phox ) and superoxide generation. Furthermore, FcgR deficiency impaired superoxide production in vivo, thus suggesting that renal oxidative stress depends on the FcgR activation in the diabetic kidney.…”

Peritubular Ischemia Contributes More to Tubular Damage than Proteinuria in Immune-Mediated Glomerulonephritis

“…It has been shown that significant loss of glomerular capillary space in WT mice is associated with marked reduction of peritubular capillary blood flow followed by a more severe degree of tubular hypoxia and thus more tubulointerstitial damage. FcRKO mice, which are protected from glomerular endothelial injury as a result of the absence of acute injury through strong activation of FcR on polymorphonuclear cells, preserved their glomerular endothelial space 23 and subsequently had a lesser degree of hypoxic insult and thus a slower decline in renal function. The intra- BASIC RESEARCH www.jasn.org vital videomicroscopy provided real-time evidence of a markedly diminished RBC velocity that closely reflects the postglomerular blood flow.…”

Requirement for Vav Proteins in Post-Recruitment Neutrophil Cytotoxicity in IgG but Not Complement C3-Dependent Injury

“…A deficiency in activating Fc␥Rs, by virtue of deletion of the common ␥-chain subunit, results in protection from several IgG-mediated, neutrophil-dependent diseases, including acute glomerulonephritis, arthritis, acute lung injury, and autoimmune skin disorders (3,4,7,8,17,18). In all of these models, a reduction in neutrophil influx was observed in mice deficient for Fc␥Rs, thus precluding conclusions about the role of these receptors in subsequent steps of neutrophil activation that lead to tissue injury.…”

“…The importance of Mac-1-mediated neutrophil cytotoxicity was defined in a model of thrombohemorrhagic vasculitis by demonstrating the absence of hemorrhage in Mac-1-deficient mice despite normal neutrophil recruitment (12). However, the contribution of neutrophil Fc␥Rs to cytotoxicity in vivo has been difficult to ascertain because genetic deficiency in activating Fc␥Rs leads to a decrease in neutrophil recruitment in all IgG mediated-inflammation models studied to date (3,8,(17)(18)(19). Thus, for Fc␥Rs, it remains unclear whether the ability of these receptors to activate neutrophil cytotoxicity vs their ability to simply bind tissue-deposited ICs to allow cellular recruitment is important in tissue injury in vivo.…”