CC Chemokine Ligand 5/RANTES Chemokine Antagonists Aggravate Glomerulonephritis Despite Reduction of Glomerular Leukocyte Infiltration

Abstract

The chemokine CC chemokine ligand (CCL)5/RANTES as well as its respective receptor CCR5 mediate leukocyte infiltration during inflammation and are up-regulated early during the course of glomerulonephritis (GN). We tested the effects of the two CCL5/RANTES blocking analogs, Met-RANTES and amino-oxypentane-RANTES, on the course of horse apoferritin (HAF)-induced GN. HAF-injected control mice had proliferative GN with mesangial immune complex deposits of IgG and HAF. Daily i.p. injections of Met-RANTES or amino-oxypentane-RANTES markedly reduced glomerular cell proliferation and glomerular macrophage infiltration, which is usually associated with less glomerular injury and proteinuria in HAF-GN. Surprisingly, however, HAF-GN mice treated with both analogs showed worse disease with mesangiolysis, capillary obstruction, and nephrotic range albuminuria. These findings were associated with an enhancing effect of the CCL5/RANTES analogs on the macrophage activation state, characterized by a distinct morphology and increased inducible NO synthetase expression in vitro and in vivo, but a reduced uptake of apoptotic cells in vivo. The humoral response and the Th1/Th2 balance in HAF-GN and mesangial cell proliferation in vitro were not affected by the CCL5/RANTES analogs. We conclude that, despite blocking local leukocyte recruitment, chemokine analogs can aggravate some specific disease models, most likely due to interactions with systemic immune reactions, including the removal of apoptotic cells and inducible NO synthetase expression.

CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets

“…An attenuation of neutrophil transmigration, however, is not necessarily protective against I/R injury, because transmigrated neutrophils as well as macrophages are suggested to play an important role during postischemic tissue remodeling and healing. 22,46,47 CD4 ϩ T cell deficiency as well as interruption of the CD40 -CD40L and CD28 -B7-dependent signaling mechanisms have a protective impact not only on hepatocellular but also on microvascular hepatic I/R injury. The postischemic breakdown of sinusoidal perfusion is considered a key factor in the pathogenesis of microvascular I/R injury.…”

Macrophage-Mediated Renal Injury Is Dependent on Signaling via the JNK Pathway

“…Similarly, many temporal studies in both immune and non-immune-initiated models of kidney disease have shown a clear association between macrophage accumulation and the development of renal injury (reviewed by Nikolic-Paterson et al [2]). However, not all studies have found concordance between increased macrophage numbers and more severe renal injury (6,7), suggesting that there may be significant functional heterogeneity within the infiltrating macrophage population. Indeed, macrophages can perform many different functions according to the local microenvironment in which they are present, ranging from a pro-inflammatory response to microbial infection to the removal of apoptotic cells, downregulation of the innate/immune response, and tissue repair.…”

Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

“…AOP-RAN-TES reduced macrophage infiltration in Thy1.1 antibody-induced glomerulonephritis in rats (11), and Met-RANTES improved rat renal allograft rejection (12). However, both antagonists aggravated immune complex glomerulonephritis in mice, which was associated with antagonist-induced modulation of macrophage function toward a proinflammatory phenotype (13).…”