KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis

Abstract

BackgroundPolarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown.MethodsWe used conditional mutant mice lacking KLF4 or TNFα (KLF4’s downstream effector) selectively in myeloid cells to investigate macrophage KLF4’s role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction.ResultsIn these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and α-smooth muscle actin in the injured kidney. CD11b+Ly6Chi myeloid cells isolated from injured kidneys expressed higher levels of TNFα mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNFα exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters.ConclusionsThese data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.

Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling

“…Macrophages exhibit remarkable plasticity that allows them to reversibly adapt themselves to changing environmental signals 60 . KLF4 not only serves as a cellular stress sensor but also has an important role in the suppression of inflammatory responses 61 . KLF4 can attenuate inflammatory responses by modulating macrophage polarization 62 , as the activation of KLF4 exerts some potential protective functions in an inflammation-related cardiac injury by modulating macrophage polarization 25 .…”

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

“…As underpinned by the data processing with the bioinformatics tool oPOSSUM, the regulatory events in Danon patients could be retraced to three main transcription factors ( Figure 1 E). In addition to the abovementioned PPRG:RXRA, KLF4 was recently described to regulate cardiac mitochondria homeostasis [ 30 ] and pro-inflammatory fibrotic injury response [ 31 ]. Similarly, SP1 was described as a key player in the induction of cardiac/cardiomyocyte fibrosis [ 29 , 62 ].…”

“…Intriguingly, these three transcription factors underpin intensive regulation of the morphological and metabolic adaptation strategies. PPARs are crucial regulators of glucose and lipid metabolism [27], SP-1 is involved in response to hypoxia [28,29] and KLF4 sustains inflammation and mitochondrial metabolic adaptation [30][31][32] and promotes senescence [33]. Indeed, mitochondria are central in determining aging phenotypes and associated metabolic states [34].…”

IRF‐1 promotes renal fibrosis by downregulation of Klotho

“…As known, TNF-α could not only induce IRF-1 expression, but also promote renal fibrosis. 40,41 As shown in Figure 5A, in HK-2 cells, TNF-α enhanced IRF-1 expression and there existed dose-dependent effect. Moreover, following TNF-α treatment in HK-2 cells, we observed a markedly decrease in C/EBP-β and Klotho expression and a dramatic increase in the expression of ɑ-SMA and fibronectin (Figure 5B,C).…”