Roquin-1 Regulates Macrophage Immune Response and Participates in Hepatic Ischemia–Reperfusion Injury

Abstract

With the development of liver surgery, ischemia-reperfusion (IR) injury has received increasing attention. Roquin-1 has been shown to play an important role in innate immune and immune balance. We demonstrate that Roquin-1 expression increased at 1 h after IR and then decreased in C57B/L mice. The immunofluorescence double-label showed that Roquin-1 was mainly expressed in macrophages (mø). Furthermore, we used clodronate liposomes to remove mø, and injected the bone marrowderived mø (BMDM) through the tail vein in 1 h before IR. We found that liver IR injury was aggravated by Roquin-1 interference. The results of PCR and ELISA suggested that after interference with Roquin-1, mø increased toward M1 and decreased toward M2. Then, interference with Roquin-1 promoted the polarization of mø to M1 and inhibited the polarization of M2. By Western blot technology and AMPKa and mTOR inhibitors, we found that Roquin-1 promotes the phosphorylation of mTOR and STAT3 by inhibiting the phosphorylation of AMPKa. We used AICAR to activate AMPKa in mø and found that the level of ubiquitination of AMPKa was decreased after activation of AMPKa. Furthermore, by bioinformatics methods, we identified potential ubiquitination sites on AMPKa. By the point mutation experiments in vitro, we confirmed that the ubiquitination of these sites is regulated by Roquin-1. Meanwhile, Roquin-1 interference inhibited the activation and function of AMPKa. This topic describes the protection of liver IR injury by Roquin-1 and discusses its main mechanism for regulating AMPKa activity through ubiquitination and affecting the polarization of mø.

Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

“…AMPK is an energy-sensing serine/threonine protein kinase that maintains cellular metabolic homeostasis [8]. Recent reports suggest that AMPK activation (phosphorylation of α subunit at thr172) and/or downstream mTOR inhibition are involved in inflammation alleviation and macrophage and/ or microglial polarization to the M2-phenotype [56][57][58]. The present study showed, for the first time, that Ac2-26 increased AMPKα phosphorylation and decreased mTOR phosphorylation in the setting of cerebral I/R, these effects were again abrogated by WRW4.…”

Eicosanoid production varies by sex in mesenteric ischemia reperfusion injury

“…Importantly, therapeutics should normalize both male and female differences as cetirizine in allergic inflammation [84]. F4/80+ macrophages, also participate in tissue injury after hepatic, myocardial, cerebral, and intestinal I/R [79][80][81][82][83]. In addition, intestines from male mice express higher levels of F4/80+ macrophages after I/R compared to intestines from female mice.…”

Lycopene alleviates hepatic ischemia reperfusion injury via the Nrf2/HO-1 pathway mediated NLRP3 inflammasome inhibition in Kupffer cells

“…For example, a study showed that MyD88-dependent activation of IL-1α in KCs promoted sterile inflammation in APAP-induced acute hepatic injury (54). Another study demonstrated that roquin-1 affected the polarization of KCs through regulating AMPKα activity following hepatic IR injury (55). Meanwhile, it has been reported that lycopene attenuated obesity-induced inflammation and insulin resistance via regulating macrophage polarization (56).…”