Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.

Abstract

Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1_{n-3 DPA} were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b⁺ integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8⁺ T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.