The role of the non-canonical NF-κB pathway during steady state and autoimmune inflammation

Abstract

The NF-κB inducing kinase (NIK) is a primary stimulator of the non-canonical NF-κB signalling pathway, which regulates many aspects of the immune response. Mutations in the NIK/Map3k14 gene have been associated with various autoimmune diseases, including multiple sclerosis (MS) and mice with germline deletion of NIK are resistant to experimental autoimmune encephalomyelitis (EAE). We found that NIK has a minimal effect on the number and activation state of microglia in the CNS during steady state. However, the NIK∆CX3CR1 mice lack a specific CD169+ macrophage population in the spleen and LNs, suggesting an essential role for the non-canonical NF-κB pathway in the development and maintenance of cells. More interestingly, our research revealed that NIK∆CX3CR1 mice exhibit resistance to EAE, with fewer immune cells infiltrating the CNS and a reduced number of activated microglia. Intriguingly, when NIK is selectively deleted in microglia using the tamoxifen-inducible CX3CR1-CreERt2 line (NIKΔMG), the resistance against EAE diminishes. This suggests that the protective effects observed in NIK∆CX3CR1 mice are not due to the absence of NIK in microglia but rather in other peripheral CX3CR1-positive cells. We further observed a reduction in the priming of T cells in the dLNs before the onset of EAE in the NIK∆CX3CR1 mice. The myeloid cell compartment of NIK∆CX3CR1 mice displayed a dysregulation in genes associated with antigen presentation and migration, along with reduced IL-23 production. Given the crucial role of IL-23 in EAE, we hypothesised that the reduced levels of IL-23 in the NIK∆CX3CR1 mice could be responsible for protection against EAE. Indeed, stimulating cells from MOG-immunised NIK∆CX3CR1 mice with IL-23 before transferring them to RAG-/- mice partly restored the EAE in these mice. Our findings indicate that NIK plays a critical role in the development and function of certain macrophages during steady state and has a crucial role in the progression of EAE by regulating many aspects of myeloid cell activation. The multitude of subtle changes within the myeloid cell compartment, such as alterations in antigen presentation genes, reduced IL-23 production, and upregulation of anti-inflammatory genes, collectively contribute to the significant EAE resistance observed in our mice. These insights provide a deeper understanding of the intricate mechanisms of immune regulation by NIK and highlight potential therapeutic targets for autoimmune diseases such as MS, offering a ray of hope for future treatments.