Irgm1 is required for the inflammatory function of M1 macrophage in early experimental autoimmune encephalomyelitis

Abstract

The classically activated (M1) macrophage has been shown to play an indispensable role in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). However, most studies focus on the effect of macrophage on CNS demyelination of EAE; whether the M1 macrophage participates in early EAE and the molecular mechanism underlying remains unclear. Here, we showed that the immunity-related GTPase family member 1 (Irgm1), also known as LRG-47, was expressed in M1 macrophages of draining lymph nodes (dLNs) from C57BL/6 mice with early EAE, and the IRGM1 heterozygote substantially reduced M1 macrophage accumulation in dLNs and spleen of the primary EAE stage. In vitro silence of IRGM1 in M1 macrophages impaired NOS2 expression and inflammatory cytokine release. We also found that IRGM1 knockout (Irgm1) in M1 macrophages increased Akt activation but attenuated NF-κB p65 activation, which may reveal Irgm1-mediated mechanisms of action. Interestingly, macrophage depletion in vivo inhibited Th1/Th17 differentiation in the spleen and promoted regulatory T cell (T) polarization in dLNs at 7 d postimmunization (dpi). Moreover, we observed that M1 macrophages in vitro promoted Th1/Th17 differentiation, which was reversed by treatment with IRGM1 small interfering RNA (siRNA), anti-TNF-α, or anti-IL-1β mAb. These results suggest that the M1 macrophage may promote Th1/Th17 cell differentiation during the early EAE, and the proinflammatory function of M1 cells requires Irgm1.

IRGM promotes glioma M2 macrophage polarization through p62/TRAF6/NF‐κB pathway mediated IL‐8 production

“…Based on the high expression of IRGM in glioma (Figures A and 1B), we supposed that IRGM regulated the formation of glioma immune microenvironment by influencing M2 GAM polarization. Although other experimental system found the role of IRGM in M1 macrophage polarization during autoimmune disease (Xu et al, ), high IRGM expression is less likely related to M1 macrophage polarization because M2 macrophage phenotype are predominant among tumor immune microenvironment. On another hand, differences of signal pathway activation between tumor cells and macrophage may lead to different function of IRGM, which will be studied in our future work.…”

“…Previous study reports, IRGM/Irgm1 is closely related to chronic infectious diseases or inflammatory bowel diseases (Song et al, ; Iida et al, ). In addition, Irgm1 regulates macrophage subset polarization and cytokines production under autoimmune disease environment (Xu et al, ). Therefore, we supposed that whether IRGM highly expressed in glioma is closely related to immunocytes of glioma patients.…”

“…Importantly, IRGM can promote tumorigenesis and cell growth in melanoma and hepatocellular carcinoma (Dong et al, ; Wang et al, ). Immunity‐related GTPase family member 1 (mouse: Irgm1; human: IRGM) promotes pro‐inflammatory macrophage subset polarization under autoimmune disease environment (Xu et al, ). IRGM looks like a cross point between immunity and tumor.…”

Activation of GPR35 protects against cerebral ischemia by recruiting monocyte-derived macrophages

“…Inhibition of PI3K/Akt signaling in synovial macrophages from rheumatoid arthritis patients is associated with increased apoptotic cell death 56 . Akt activation in macrophages results in reduced severity in experimental autoimmune encephalomyelitis 57 . Akt signaling was implicated in neuroprotection after stroke 13 .…”

LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling

“…In the present study, we found that LRG-1, a kind of secretive glycoprotein, could serve as an efficient biomarker for predicting the prognosis of PDAC patients. LRG-1 has been proven to be associated with inflammation and autoimmune disease in the past few years [40, 41]. Shinzaki et al demonstrated that LRG-1 was a serum biomarker of mucosal healing in ulcerative colitis (UC) and serum LRG-1 concentrations in active UC patients was significantly higher than that in patients who had complete mucosal healing and deep remission [40, 42].…”