Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis

t•Plasma IL-1RA is correlated with EDSS independent of age, sex, disease duration, and time since most recent MS relapse IL-1RA is correlated with NfL levels in CSF.•NLRP3 inflammasome activation results in IL-1RA release from primary human macrophages and microglia.•IL-1RA is expressed in myeloid-derived cells within mixed active/inactive MS lesions•IL-1RA is an exploratory biomarker that may be used to monitor disability independently of relapse activity. Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1β known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF). Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1β were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue. Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA+ macrophages/microglia were present at the rim of mixed active/inactive MS lesions. Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.