Microglia promote autoimmune inflammation via the noncanonical NF-κB pathway

Area of Science:

• Neuroimmunology
• Cellular and Molecular Neuroscience

Background:

• Microglia are key immune cells in the central nervous system (CNS).
• Neuroinflammation, mediated by microglia, is central to diseases like multiple sclerosis and its model, EAE.
• The noncanonical nuclear factor kB (NF-κB) pathway's role in microglial function during neuroinflammation is not fully understood.

Purpose of the Study:

• To investigate the role of the noncanonical NF-κB pathway in microglia during EAE pathogenesis.
• To determine if microglial noncanonical NF-κB-inducing kinase (NIK) signaling is essential for EAE progression.

Main Methods:

• Utilized a mouse model of experimental autoimmune encephalomyelitis (EAE).
• Generated microglia-specific NIK knockout mice to assess the role of microglial NIK.
• Analyzed T cell and monocyte infiltration into the CNS.
• Investigated the interplay between T cell-derived cytokines and microglial signaling pathways.

Main Results:

• Microglia-specific deletion of NIK significantly impaired EAE disease progression.
• Microglial NIK was not essential for initial T cell infiltration or disease onset.
• Microglial NIK was critical for the subsequent recruitment of inflammatory T cells and monocytes to the CNS.
• T cell activation of microglial noncanonical NF-κB signaling, in synergy with granulocyte-macrophage colony-stimulating factor, drives chemokine expression for sustained inflammation.

Conclusions:

• Microglial noncanonical NF-κB signaling, mediated by NIK, is a critical driver of EAE progression.
• This pathway is essential for amplifying neuroinflammation through the recruitment of secondary inflammatory cells.
• Targeting microglial NIK-dependent pathways may offer therapeutic strategies for neuroinflammatory diseases like MS.