NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients

Abstract

Primary progressive multiple sclerosis is a poorly understood disease entity with no specific prognostic biomarkers and scarce therapeutic options. We aimed to identify disease activity biomarkers in multiple sclerosis by performing an RNA sequencing approach in peripheral blood mononuclear cells from a discovery cohort of 44 untreated patients with multiple sclerosis belonging to different clinical forms and activity phases of the disease, and 12 healthy control subjects. A validation cohort of 58 patients with multiple sclerosis and 26 healthy control subjects was included in the study to replicate the RNA sequencing findings. The RNA sequencing revealed an interleukin 1 beta (IL1B) signature in patients with primary progressive multiple sclerosis. Subsequent immunophenotyping pointed to blood monocytes as responsible for the IL1B signature observed in this group of patients. Functional experiments at baseline measuring apoptosis-associated speck-like protein containing a CARD (ASC) speck formation showed that the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome was overactive in monocytes from patients with primary progressive multiple sclerosis, and canonical NLRP3 inflammasome activation with a combination of ATP plus lipopolysaccharide was associated with increased IL1B production in this group of patients. Primary progressive multiple sclerosis patients with high IL1B gene expression levels in peripheral blood mononuclear cells progressed significantly faster compared to patients with low IL1B levels based on the time to reach an EDSS of 6.0 and the Multiple Sclerosis Severity Score. In agreement with peripheral blood findings, both NLRP3 and IL1B expression in brain tissue from patients with primary progressive multiple sclerosis was mainly restricted to cells of myeloid lineage. Treatment of mice with a specific NLRP3 inflammasome inhibitor attenuated established experimental autoimmune encephalomyelitis disease severity and improved CNS histopathology. NLRP3 inflammasome-specific inhibition was also effective in reducing axonal damage in a model of lipopolysaccharide-neuroinflammation using organotypic cerebellar cultures. Altogether, these results point to a role of IL1B and the NLRP3 inflammasome as prognostic biomarker and potential therapeutic target, respectively, in patients with primary progressive multiple sclerosis.

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

“…A recent study identified that NLRP3 was overexpressed in the monocytes of primary progressive MS patients when compared to healthy controls. Furthermore, in this study the rate of MS progression correlated with the degree of IL-1β elevation in peripheral monocytes via RNA sequencing [88]. The utility of NLRP3 as a potential biomarker in MS is further supported by another study demonstrating elevated NLRP3 in neuromyelitis optica spectrum disorders [89].…”

Microglial inflammasome activation drives developmental white matter injury

“…We now demonstrate that inflammasome inhibition reinstates myelination in developing white matter, a strategy previously shown to dampen injury to neurons in development (Chen, Xu, & Yuan, 2018;Girard et al, 2012;Leitner et al, 2014) and to white matter in adulthood (Cantuti-Castelvetri et al, 2018;Malhotra et al, 2020).…”

Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

“…Activated astrocytes elicit neuroinflammation and release inflammatory cytokines such as IL-1β [15], which leads to axonal hypomyelination [16]. Recent studies showe that NLRP3 considers to be crucial for secretion of IL-1β [17,18]. The results showed a remarkable increase in the levels of IL-1β and NLRP3 in BCCAO rats up to 1 day.…”