Relaxin abrogates renal interstitial fibrosis by regulating macrophage polarization via inhibition of Toll-like receptor 4 signaling

Abstract

Renal fibrosis is a common feature of chronic kidney disease (CKD). To inhibit the CKD process, it is important to prevent renal fibrosis, though CKD remains incurable. Renal fibrosis can be inhibited by relaxin in several experimental models, but the mechanism of relaxin for antifibrotic potential is still not clear. And here we have studied the role of relaxin in macrophage polarization and renal inflammation after unilateral ureteral obstruction (UUO). Our results show that relaxin can downregulate the Toll-like receptor (TLR) 4 signaling, shift macrophage polarization toward the M2 phenotype and ameliorat renal fibrosis in the early stages of UUO. In vitro experiments, it has been confirmed that relaxin can downregulate the TLR4 signaling and induce the M2 macrophage transition. Furthermore, the transitional actions of macrophage phenotype induced by relaxin are significantly blocked by TAK-242, a TLR4 antagonist, in vitro experiments. Thus, there is a novel mechanism of relaxin for antifibrosis that shifts macrophage polarization toward the M2 phenotype via inhibition of TLR4 signaling.

Celastrol treatment protects against acute ischemic stroke-induced brain injury by promoting an IL-33/ST2 axis-mediated microglia/macrophage M2 polarization

“…Previous studies have implicated IL-33/ST2 axis in downregulation of TLR signaling [ 29 ]. The activation of TLR signaling can shift macrophage polarization toward the M1 phenotype [ 30 ]. But if TLR signaling is involved in IL-33/ST2 axis-mediated macrophage polarization, regulation is still unclear.…”

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

“…Recombinant H2 relaxin was generously provided by Corthera Inc (San Carlos, CA, USA; a subsidiary of Novartis AG, Basel, Switzerland) and is bioactive in rats 21,22,24,25,[38][39][40] and mice 15,19,25,39,41,42 . A rat and mouse model of UUO, which mimics the pathology of human progressive renal disease 43,44 , was used as an experimental model of primary tubulointerstitial fibrosis.…”

“…[12][13][14][15] Additionally, RLX can inhibit inflammatory cell influx post-injury [16][17][18] and influence macrophage polarization towards a M2 pro-repair macrophage phenotype. 19 Signal transduction studies have shown that activation of RXFP1 on renal and cardiac myofibroblasts by RLX directly increases cGMP 20 or signals through an ERK1/2 phosphorylation and neuronal nitric oxide (NO) synthase (nNOS)-NO-sGC-cGMP-dependent pathway to inhibit TGF-1 signal transduction at the level of intracellular Smad2 phosphorylation (phospho-Smad2). 13,[21][22][23] This in turn disrupts the pro-fibrotic actions of TGF-1 on myofibroblast differentiation and aberrant ECM deposition.…”

Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

“…Furthermore, relaxin decreases granule exocytosis and mast cell degranulation to reduce proinflammatory and allergic cytokines such as histamine, leukotrienes and serotonin . Relaxin can also inhibit the endothelial adhesiveness to neutrophils and the infiltration of macrophages which are crucial for the recruitment and migration of inflammatory cells to the site of injury (Hewitson et al, 2007;Martin et al, 2018;Nistri et al, 2003), inhibit toll-like receptor-4 signaling, and promote tissue-repairing M2 macrophage polarization (Chen et al, 2017). Moreover, relaxin inhibits NLRP3 inflammasome activity, which is known to increase interleukin (IL)-1β activity (Raleigh et al, 2017), and also plays a role in inhibiting NFkB signaling, a crucial transcription factor that regulates many inflammatory genes (Martin et al, 2018).…”