Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis

Abstract

A hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effect of a selective STAT6 inhibitor, AS1517499, on myeloid fibroblast activation, macrophage polarization, and development of renal fibrosis in two experimental murine models. To investigate the effect of STAT6 inhibition on myeloid fibroblast activation, macrophage polarization, and kidney fibrosis, wild-type mice were subjected to unilateral ureteral obstruction or folic acid administration and treated with AS1517499. Mice treated with vehicle were used as control. At the end of experiments, kidneys were harvested for analysis of myeloid fibroblast activation, macrophage polarization, and renal fibrosis and function. Unilateral ureteral obstruction or folic acid administration induced STAT6 activation in interstitial cells of the kidney, which was significantly abolished by AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with ureteral obstruction or folic acid nephropathy compared with vehicle-treated mice. Moreover, AS1517499 significantly suppressed M2 macrophage polarization in the injured kidney. Furthermore, AS1517499 markedly reduced the expression levels of extracellular matrix proteins, and development of kidney fibrosis and dysfunction. These findings suggest that AS1517499 inhibits STAT6 activation, suppresses myeloid fibroblast activation, reduces M2 macrophage polarization, attenuates extracellular matrix protein production, and preserves kidney function. Therefore, targeting STAT6 with AS1517499 is a novel therapeutic approach for chronic kidney disease.

The role of the macrophage-to-myofibroblast transition in renal fibrosis

“…Recent studies have shown that STAT6 could suppress M2 macrophage polarization and be involved in the monocyte-to-fibroblast transition in folic acid nephropathy (33). Furthermore, STAT6-specific inhibitor (AS 1517499) has been proven to prevent M2 macrophage polarization and transformation of myofibroblasts, which lead to a reduction of collagen deposition and ECM production in the injured kidney (34). This evidence supports that JAK3/STAT6 signaling takes a crucial part in renal fibrosis via regulating the MMT.…”

Pharmacological Inhibition of STING/TBK1 Signaling Attenuates Myeloid Fibroblast Activation and Macrophage to Myofibroblast Transition in Renal Fibrosis

“…Our previous studies have shown that FA treatment can cause severe fibrosis and renal dysfunction of mice at the end of 14 days ( Liang et al, 2017a ; Chen et al, 2021a ; Liu et al, 2021b ). The activation of myeloid fibroblasts and transition of macrophages to myofibroblasts are proved to be critical factors that contribute to progression of kidneys fibrosis ( Jiao et al, 2021a ; Jiao et al, 2021b ; Liu et al, 2021b ). However, the molecular signaling mechanisms that trigger bone marrow-derived fibroblasts activation and promote macrophages to myofibroblasts differentiation are not completely understood.…”

“…Bone marrow–derived fibroblast precursors express hematopoietic markers such as CD45 ( Liang et al, 2017a ). In response to persistent inflammatory stimuli, bone marrow-derived fibroblasts are activated and further differentiate into myofibroblasts ( Liang et al, 2017a ; Jiao et al, 2021a ; Jiao et al, 2021b ). Of note, STING has an important role in the regulation of bone marrow-derived macrophages activation ( Yan et al, 2018 ).…”

“…Our findings show that pharmacological inhibition by H-151 impedes the transition of macrophages to myofibroblasts in progressive kidney fibrosis, suggesting STING has a critical role in the modulation of MMT in FA nephropathy. Numerous studies have documented that M2 macrophages promote kidney fibrosis by producing numbers of pro-fibrotic factors and triggers fibroblast activation ( Feng et al, 2018 ; Jiao et al, 2021a ; Jiao et al, 2021b ; Li et al, 2021 ). In addition, the cells involved in MMT are mainly M2-like phenotype ( Zhang et al, 2016 ; O'Brien and Spiller, 2021 ).…”

The Intersection of Acute Kidney Injury and Non-Coding RNAs: Inflammation

“…Notably, however, macrophages can also promote renal fibrosis, which is a major driver of progression to end-stage AKI. For instance, recent studies suggest that the role of M2 macrophages in chronic kidney disease may be the opposite of that in AKI, and targeting signal transducer and activator of transcription 6 (STAT6) can inhibit the polarization of M2 macrophages, thereby protecting renal function ( Jiao et al, 2021a ; Jiao et al, 2021b ). Elucidating the exact role and timing of M2 activation is thus imperative to stunt the progression of AKI.…”