Inhibition of Glycolytic Reprogramming Suppresses Innate Immune-mediated Inflammation in Experimental Amyotrophic Lateral Sclerosis

Overview

Journal Inflamm Res

Specialties Allergy & Immunology
Pathology

Date 2024 Aug 21

PMID 39167140

Authors

Lewis Yu

Nancy Wu

Okmi Choi

Khoa Dinh Nguyen

Affiliations

Soon will be listed here.

Abstract

Background: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.

Methods: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.

Results: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45 infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45 microglia and F4/80 + CD45 infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.

Conclusions: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

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