Elevated expression of the NLRP3 inflammasome in post-mortem brain white matter and immune cells in multiple sclerosis

BACKGROUND: The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a signalling hub associated with the pathogenesis of neuroinflammatory conditions such as multiple sclerosis (MS). NLRP3 inflammasome activation requires interplay between pathogen-/damage-associated molecular patterns and other soluble factors, which initiates inflammation to promote the secretion of the cytokine, interleukin (IL)-1β. OBJECTIVE: To determine if the expression of NLRP3 inflammasome signalling components is altered in the brain and in immune cells in MS. METHODS: Using post-mortem brain tissue from 21 cases, including 8 non-MS control, 7 primary progressive (PP) MS and 6 secondary progressive (SP) MS cases, alongside peripheral blood mononuclear cells (PBMCs) isolated from 45 subjects including healthy controls (n = 23), and people with (pw) a relapsing remitting (RR) (n = 15), SP (n = 5) or PP (n = 2) form of MS, we profiled the expression of NLRP3 inflammasome components, both centrally in CNS white matter, and peripherally in immune cells. RESULTS: The expression of NLRP3, IL1B, IL18, CASP1 and PYCARD transcripts were elevated in chronic active lesions (CALs) in PPMS cases, with no significant alterations determined in SPMS CNS tissue. Furthermore, NLRP3-dependent IL-1β release, alongside NLRP3, IL1B and GSDMD expression, were significantly elevated in immune cells isolated from pwMS (primarily RRMS), when compared to PBMCs from healthy controls. CONCLUSION: The expression of NLRP3 inflammasome components is dysregulated in MS, both in the brain and in PBMCs. This suggests that uncontrolled NLRP3 inflammasome activity takes place at certain stages of MS.