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.

Background & aims COVID-19 is a severe viral infection of the respiratory tract and become a worldwide pandemic. Months after the initial infection several people report persistent limitations in daily life. Previous studies have identified body composition as a predictor of clinical progression in cases of COVID-19. However, body impedance measurements were limited to baseline and not repeated in serial measurements. In this study we analyzed the impact of a moderate oxygen-dependent COVID-19 infection on body composition during hospitalization. Methods We enrolled 12 consecutive patients hospitalized due to an oxygen-dependent SARS-CoV-2 infection. Body impedance analysis was performed within 24 hours of admission and repeated on day 3 ± 1 as well as on the day of discharge. Endpoints were any significant changes in body composition. Results Median age of enrolled patients was 70.6 years with a BMI of 30.8 kg/m 2 . Patients were hospitalized for 14 days. Median oxygen demand was 3 l/min, 2 patients required mechanical ventilation. Body water and fat remained unchanged during the study period. We observed a significant decrease of phase angle (-0.6, p<0.01) and body cell mass (-2.3%, p<0.01) with an increase in extracellular mass on day 3. Values returned to baseline along recovery. Conclusion We found a significant reduction in body cell mass and phase angle during the active infection with slow regression towards hospital discharge. Future studies are needed to clarify if nutrition and training programs during and after COVID-19 might limit these changes and have a positive impact on clinical course and rehabilitation.

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.

The nephrotoxic serum nephritis (NTN) model is an integral part of experimental glomerulonephritis (GN) research. Here, we discuss how the murine NTN model can be induced and effectively used to mimic an immune complex-mediated GN. Further, we differentiate between heterologous and autologous models by comparing pathophysiology and phenotypic manifestations.

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