Microglia promote autoimmune inflammation via the noncanonical NF-κB pathway

Abstract

Microglia have been implicated in neuroinflammatory diseases, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). We demonstrate that microglia mediate EAE disease progression via a mechanism relying on the noncanonical nuclear factor kB (NF-B) pathway. Microglia-specific deletion of the noncanonical NF-B-inducing kinase (NIK) impairs EAE disease progression. Although microglial NIK is dispensable for the initial phase of T cell infiltration into the central nervous system (CNS) and EAE disease onset, it is critical for the subsequent CNS recruitment of inflammatory T cells and monocytes. Our data suggest that following their initial CNS infiltration, T cells activate the microglial noncanonical NF-B pathway, which synergizes with the T cell-derived cytokine granulocyte-macrophage colony-stimulating factor to induce expression of chemokines involved in the second-wave of T cell recruitment and disease progression. These findings highlight a mechanism of microglial function that is dependent on NIK signaling and required for EAE disease progression.

Novel Insights into the Emerging Role of Neat1 and Its Effects Downstream in the Regulation of Inflammation

“…148 Furthermore, microglia can mediate experimental autoimmune encephalomyelitis, a neuroinflammatory disorder, and pathogenesis progression, therein, T cells activate the microglial noncanonical NF-κB pathway plays a crucial role. 149 As aforementioned, LncRNA can act on mRNA indirectly through miRNA or mRNA, and there is such a relationship between Neat1 and NF-κB. Xiao et al 150 demonstrated that Neat1 was up-regulated in rheumatoid arthritis, a chronic inflammatory disease, and the knockdown of it attenuated TNF-α-induced cell proliferation and inflammatory cytokine production while promoting cell apoptosis by targeting miR-204-5p through activating the NF-κB signaling pathway.…”

Strategies for Manipulating Microglia to Determine Their Role in the Healthy and Diseased Brain

“…Specifically, microglia-specific TAK1 or NIK1 depletion has been shown to affect the activation of proinflammatory pathways through the NF-kB pathway, and result in animals resistant to EAE. However, appropriate T cell responses were found in the periphery [85,86]. The TAK1 deletion also attenuated CCL2 expression leading to decreased infiltration by inflammatory monocytes, while the NIK1 deletion attenuated the infiltration by T cells.…”

Microglial Dysfunction in Neurodegenerative Diseases via RIPK1 and ROS

“…It therefore decreases the number of CNS-infiltrating T cells and ameliorates EAE disease scores in the late phase of MS. These results indicate that the non-canonical NF-κB pathway is activated and essential for microglia to promote neuroinflammation during MS pathogenesis [ 29 ].…”