Innate lymphoid cells: unsung heroes or villains in multiple sclerosis pathogenesis?

The emerging role of Innate Lymphoid Cells (ILCs) in the pathogenesis and regulation of Multiple Sclerosis (MS), a complex neuroinflammatory autoimmune disease, has been increasingly recognized. Once identified only for activities conducted at barrier surfaces, ILCs are now understood to be important modulators of inflammation and tissue repair within the Central Nervous System (CNS). This review aims to elucidate the 'two sides of the coin' nature of ILCs in MS. ILCs are implicated in pathogenesis by driving neuroinflammation through pro-inflammatory cytokines, contributing to the formation of ectopic meningeal lymphoid follicles, and modulating meningeal immune system interactions. In contrast, certain ILC subsets confer protective effects by secreting anti-inflammatory cytokines and promoting tissue homeostasis. Recent experimental and clinical studies have demonstrated the complex balance and alteration of ILC responsiveness at various stages of MS. We focused on the importance of ILC subset determination, including their dependence on key cytokine signaling pathways and their critical role in the gut-CNS axis, a pivotal mediator of systemic immunity in MS. Moreover, the potential for ILC pathway targeting, either by modulating cytokine networks or modifying the microbiota, is discussed as a promising avenue for restoring immune balance, promoting neuroprotection and suppressing ILC-driven inflammation. Despite the challenges presented by ILC plasticity and diversity, elucidating ILC biology offers a clear path toward developing precise immunomodulatory strategies aimed at halting disease progression and promoting CNS repair in patients with MS.