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Age-dependent microglial disease phenotype results in functional decline in gut macrophages

Open AccessPublished:September 28, 2022DOI:https://doi.org/10.1016/j.gastha.2022.09.006
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      Abstract

      Background & Aims

      Muscularis macrophages (MMs) are tissue resident macrophages in the gut muscularis externa that provide a supportive role to the enteric nervous system (ENS). We have previously shown that age-dependent MM alterations drive low-grade ENS inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline.

      Methods

      Young (3 months) and old (16-24 months) C57BL/6 mice and human tissue were studied. Immune cells from mouse small intestine, colon and spinal cord, and human colon were dissociated, immunophenotyped by flow cytometry, and examined for gene expression by single cell RNAseq and quantitative RT-PCR. Phagocytosis was assessed by in vivo injections of pHrodo beads. Macrophage counts were performed by immunostaining of muscularis whole mounts.

      Results

      MMs from young and old mice express homeostatic microglial genes, including Gpr34, C1qc, Trem2 and P2ry12. An MM subpopulation that becomes more abundant with age, assumes a geriatric state (GS) phenotype characterized by increased expression of disease-associated microglia (DAM) genes including CD9, CLEC7A, Itgax (CD11c), Bhlhe40, Lgals3, IL-1β, and Trem2, and diminished phagocytic activity. Acquisition of the GS phenotype is associated with clearance of α-synuclein (α-SYN) aggregates. Human MMs demonstrate a similar age-dependent acquisition of the GS phenotype associated with intracellular α-SYN accumulation.

      Conclusion

      MMs demonstrate age-dependent genetic changes that mirror the microglial DAM phenotype and result in functional decline.

      Keywords

      Abbreviations:

      DAM (disease-associated microglia), ENS (enteric nervous system), GS (geriatric state), HS (homeostatic state), LpM (lamina propria macrophage), MM (muscularis macrophage)