Abstract
Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)–mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4−/− mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo, a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4−/− mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies.
Highlights
Renal ischemia reperfusion injury (IRI) refers to the damage that occurs from interruption and the subsequent restoration of blood flow to the kidney
Replicating and expanding our previous reports [19], we found interferon regulatory factor 4 (IRF4) to be mainly expressed in myeloid cells, with the highest expression in CD11b+ cells
In the acute phase of IRI, IRF4 acts as an endogenous regulator of myeloid cell activation, i.e., dendritic cells, suppresses TNF-α release from intrarenal myeloid cells, and thereby limits tubular cell necrosis, tissue inflammation, and acute renal failure 24 h and 5 days post-IRI [19]
Summary
Renal ischemia reperfusion injury (IRI) refers to the damage that occurs from interruption and the subsequent restoration of blood flow to the kidney. Hypoxia that develops upon IRI results in irreversible damage to tubular cells in the S3 segment of the nephrons and an excessive innate immune response, i.e., necroinflammation [1]. The area exposed to injury, immunologic factors, and genetic factors determine the degree of irreversible nephron loss and subsequent scarring. It is still not clear how to estimate the long-term outcome in patients following acute kidney injury (AKI). The importance of some negative regulators of inflammation remains not well-established with respect to long-term outcome following chronic post-ischemic AKI. Long-term cohort studies indicate that AKI is an underestimated yet significant risk factor for chronic kidney disease (CKD) [2]. Identification of molecular and cellular mechanisms involved in the transition from acute to chronic renal injury might constitute an important step on the way to new therapeutic approaches
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