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

Abstract

Following renal ischemia-reperfusion injury (IRI), resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. Atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor that binds and scavenges inflammatory CC chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared with wild type, Ackr2 deficiency increases CC chemokine ligand 2 levels in tumor necrosis factorestimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI 1 or 5 days after transient renal pedicle clamping, tubular injury was similar to wild type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2 À/À kidneys. Regarding long-term outcomes, Ackr2 À/À kidneys displayed more tubular injury 5 weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6C high inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency caused substantially aggravated renal fibrosis in Ackr2 À/À kidneys 5 weeks after IRI, shown by increased expression of matrix molecules, renal accumulation of a-smooth muscle actinepositive myofibroblasts, and bone marrowederived fibrocytes. ACKR2 is important in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury and, thus, can prevent progression to chronic renal disease.

Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

“…Ackr2 can internalize chemokines for degradation which reduces chemokine availability, inhibits leukocyte infiltration, and promotes immune resolution and adaptive immunity. However, the functions of Ackr2 may be context-dependent, and may be pathologic 29,83,84 or protective 29 in different disease models 85 . Genetic deletion of Ackr2 attenuates albuminuria, leukocyte infiltration, and interferonrelated pathways (e.g.…”

Covid‐19 and kidney injury: Pathophysiology and molecular mechanisms

“…57 Previous studies indicated that ACKR2 limits the infiltration of leucocyte, inflammation, and remodelling of fibrotic tissue following AKI; therefore, avoiding the progression of the disease. 71 Moreover, regarding the preventive role of ACKR2 in limiting kidney injury progression, it might be a promising target for renal inflammatory and fibrotic disease associated with AKI. 72 As a life-threatening organ dysfunction, sepsis is a serious complication in cases with novel SARS-CoV-2 pneumonia caused by a cytokine storm cascade following the infection.…”

The kidney, COVID-19, and the chemokine network: an intriguing trio

“…Accordingly, the established ACKR2 knockout mouse exhibits several features of human diabetic nephropathy and extensive renal inflammation [58]. A recent report also showed that ACKR2 limits leukocyte infiltration (mainly monocytes, T-lymphocytes, and Ly6Chi inflammatory macrophages), inflammation, and fibrotic tissue remodeling after AKI, thus preventing progression to chronic kidney disease [59]. Furthermore, it has been demonstrated that ACKR2 plays an important role in limiting glomerular and tubulointerstitial injury, inflammation, and fibrotic remodeling due to scavenging of chemokines in the tubulointerstitial compartment [60].…”