The atypical chemokine receptor 2 limits renal inflammation and fibrosis in murine progressive immune complex glomerulonephritis

Abstract

The atypical chemokine receptor 2 (ACKR2), also named D6, regulates local levels of inflammatory chemokines by internalization and degradation. To explore potential anti-inflammatory functions of ACKR2 in glomerulonephritis, we induced autologous nephrotoxic nephritis in C57/BL6 wild-type and Ackr2-deficient mice. Renal ACKR2 expression increased and localized to interstitial lymphatic endothelium during nephritis. At two weeks Ackr2mice developed increased albuminuria and urea levels compared to wild-type mice. Histological analysis revealed increased structural damage in the glomerular and tubulointerstitial compartments within Ackr2 kidneys. This correlated with excessive renal leukocyte infiltration of CD4 T cells and mononuclear phagocytes with increased numbers in the tubulointerstitium but not glomeruli in knockout mice. Expression of inflammatory mediators and especially markers of fibrotic tissue remodeling were increased along with higher levels of ACKR2 inflammatory chemokine ligands like CCL2 in nephritic Ackr2 kidneys. In vitro, Ackr2 deficiency in TNF-stimulated tubulointerstitial tissue but not glomeruli increased chemokine levels. These results are in line with ACKR2 expression in interstitial lymphatic endothelial cells, which also assures efflux of activated leukocytes into regional lymph nodes. Consistently, nephritic Ackr2 mice showed reduced adaptive cellular immune responses indicated by decreased regional T-cell activation. However, this did not prevent aggravated injury in the kidneys of Ackr2 mice with nephrotoxic nephritis due to simultaneously increased tubulointerstitial chemokine levels, leukocyte infiltration and fibrosis. Thus, ACKR2 is important in limiting renal inflammation and fibrotic remodeling in progressive nephrotoxic nephritis. Hence, ACKR2 may be a potential target for therapeutic interventions in immune complex glomerulonephritis.

The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury

“…Protein levels of the proinflammatory chemokines CCL2, CCL5, and CXCL10 were significantly elevated in postischemic Ackr2 À/À kidneys ( Figure 6A). Together with our previous findings demonstrating increased CCL2 levels in tumor necrosis factor-aestimulated Ackr2-deficient tubulointerstitial tissue in vitro, 27 these results are consistent with a defect in chemokine clearance in Ackr2-deficient kidneys. In addition, chemokines expressed by the higher number of attracted leukocytes may subsequently contribute to increased renal levels.…”

“…In control and ischemic kidneys, in situ hybridization analysis localized the expression of Ackr2 mRNA transcripts specifically to endothelial cells of the tubulointerstitium ( Figure 1C), which were recently identified as LYVE-1epositive lymphatic endothelium. 27 Consistently, increased CCL2 levels were demonstrated in supernatants of Ackr2-deficient tubulointerstitial cells, but not glomeruli, compared with wild type on tumor necrosis factor-a stimulation in vitro. 27 Similar to its reported function in skin, lung, and heart, 12e14 these data suggest that renal ACKR2 expressed by tubulointerstitial lymphatic endothelial cells could scavenge chemokines produced in the tubulointerstitial compartment and, thus, may play an important role in limiting inflammatory responses after AKI.…”

“…Comparable anti-inflammatory and antifibrotic effects of ACKR2 were recently reported in mice with immune complex glomerulonephritis that was induced by injection of nephrotoxic serum. 27 Taken together, these data suggest an important general role for ACKR2 in limiting ongoing inflammation and fibrotic tissue remodeling in the kidney after an episode of renal injury. However, a recent study in diabetic OVE mice found that Ackr2 deficiency resulted in renal protection, reduced leukocyte infiltration, and decreased renal fibrosis at 6 months.…”

“…In wild-type mice, renal ACKR2 expression was significantly induced after IRI and was localized to endothelial cells of the tubulointerstitium. Previously, increased CCL2 levels have been noticed in the supernatants of Ackr2-deficient tubulointerstitial tissue but not glomeruli on stimulation with tumor necrosis factor-a, 27 which contributes to renal damage after IRI. 37e39 These observations are consistent with a reduced ability of Ackr2 À/À tissue to locally scavenge and degrade chemokines, and with the expression of ACKR2 on lymphatic endothelial cells, 11 which in the kidney are present in the tubulointerstitium, but not in glomeruli.…”

Koebner phenomenon leading to the formation of new psoriatic lesions: evidences and mechanisms

“…ACKR2, also named as D6, plays a vital role in controlling inflammatory reactions as these receptors serve as scavengers for proinflammatory cytokines and chemokines [110]. Due to their inflammatory regulatory functions, ACKR2 limits the spreading of psoriasiform skin inflammation to the remote body area [111].…”