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Infiltration of monocyte-derived macrophages perturbs the CNS metabolic landscape, licensing arginine catabolism and augments neuro-inflammation

ABSTRACT: Inflammatory responses are associated with monocyte recruitment into inflamed tissues, where they differentiate into monocyte-derived macrophages (moMACs). While tissue-specific reprogramming of moMACs is well-established, how they alter tissue metabolism remains unclear. Here, using a murine neuro-inflammation model coupled with genetic fate-mapping, metabolomics and metabolite imaging, we identify that central nervous system (CNS) moMACs infiltration is associated with substantial metabolic changes, assigning disease-associated metabolites (DAMs) therein. Particularly, we found decreased arginine levels due to increased arginine catabolism driven by lesion-associated arginase 1 (Arg1) expressing moMACs. Arg1-expressing moMACs were linked to disease severity and via their impacts on arginine were engaged in lipid-metabolism and pro-inflammation. Genetic Arg1 deficiency within moMACs during neuro-inflammation increased extracellular arginine, improved outcome, and resulted in rewiring of the CNS metabolic landscape, associated with attenuated DAMs and regulatory T-cell expansion. Together, we demonstrate key roles for moMACs-driven arginine catabolism in neuro-inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE231474 | GEO | 2024/05/02

REPOSITORIES: GEO

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Project description:Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.

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Infiltration of monocyte-derived macrophages perturbs the CNS metabolic landscape, licensing arginine catabolism and augments neuro-inflammation

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