Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis. Issue 133 (December 2022)

• Record Type: Journal Article
• Authors: Ren, Kaixi; Li, Sanzhong; Liang, Shiqian; Fan, Fan; Lu, Jiarui; Wei, Tiaoxia; Cao, Xiuli; Gong, Li; Li, Hongzeng; Zhao, Junlong; Qin, Hongyan; Guo, Jun
• Is Part Of: Journal of autoimmunity. Issue 133(2022)
• Publication Date: 2022-12
• Subjects: Immune-mediated neuropathies -- Guillain-Barré syndrome -- Experimental autoimmune neuritis -- Monocyte conversion -- Notch signaling -- NR4A1; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2022.102945
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Monocytes in peripheral blood and sciatic nerves play vital roles in immune-mediated neuropathies such as Guillain-Barré syndrome (GBS). Different subpopulations of monocytes, including classical and non-classical, exhibit distinct functions as well as phenotypic conversion potentials. However, the mechanisms underlying their development during immune-mediated neuropathy remain unclear. Notch signaling participates in monocyte differentiation and function. In this study, we used a myeloid-specific Notch signaling activation transgenic mouse (NIC cA ) and investigated the role of Notch signaling in monocytes during experimental autoimmune neuritis (EAN) in a mouse model of GBS. Clinical score assessment and histopathological examination revealed that sciatic nerve injury was attenuated in NIC cA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6C lo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NIC cA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NIC cA mice are more inclined toward Ly6C lo cells than Ly6C hi cells. Differential expression of monocyte development-associated genes was detected in NIC cA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NIC cA mice-derived monocytes compromise their Ly6C lo tendency. Consistently, a relationship between monocyte conversion and disease severity was observed in blood samples from patients with GBS. In conclusion, our current study showed that monocyte conversion modulated by Notch signaling plays an essential role in the EAN mouse model. Highlights: Monocytes increase robustly during immune-mediated neuropathies and are related to disease severity. Notch signaling activation in myeloid cells alleviates nerve injuries in mouse experimental autoimmune neuritis. Notch signaling activation promotes monocytes phenotype conversion. Notch signaling-related factors interact with NR4A1 to mediate monocyte conversion.