Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis

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.