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Aging Impairs Macrophage Phagocytosis through Mitochondrial ROS-Induced Collagen Production

ABSTRACT: Macrophages are pivotal immune cells due to their phagocytic capabilities, yet the impact of aging on macrophage phagocytosis remains poorly understood. Using comprehensive in vitro and in vivo phagocytic assays, we demonstrate significantly reduced phagocytic activity in monocyte-derived macrophages from aged humans and mice compared to young counterparts. RNA-seq analysis revealed upregulated expression of extracellular matrix protein genes, particularly collagens, in aged macrophages, manipulation of COL1A1 expression can significantly affect phagocytosis. Protein interaction assay identified binding between collagen and actin filaments, which inhibits F-actin turnover and consequently impairs phagocytic function. Also, we found that mitochondrial ROS is the driving force of collagen overproduction and MitoTEMPO rejuvenates macrophage phagocytosis via restoring actin dynamics. In mouse model, MitoTEMPO significantly boosted the phagocytosis of peritoneal macrophage against bacteria. These findings highlight the fundamental role of mitochondrial redox balance and collagen production in controlling macrophage phagocytic function, identifying them as targetable mechanisms for promoting healthy immune aging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306336 | GEO | 2026/06/24

REPOSITORIES: GEO

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Project description:Phagocytosis requires the activation of a plethora of mechanisms that include the activation of the actin cytoskeleton guided by the Arp2/3 complex. These are promoted by activators such as the Wiskott Aldrich Syndrome Protein (WASP) family members. In order to further understand the molecular mechanisms involved in the early events leading the phagocytosis of the pathogenic Mycobacterium tuberculosis, we set out to examine potential roles of miRNAs in phagocytosis using genome-wide expression profiling to identify miRNAs differentially regulated following mycobacterial infection. One of the miRNAs activated upon infection of mouse macrophages with the non-pathogenic Mycobacterium smegmatis, the widely conserved miR-142-3p, was predicted and confirmed to target the Neural-WASP (N-WASP). Upregulating of miR-142-3p in mouse macrophages inversely correlated with levels of N-WASP, upon infection with live pathogenic and non-pathogenic mycobacteria, suggesting an active role of Mycobacterium tuberculosis on the regulation of phagocytosis, at the post-transcriptional level, in host cells. The reduction of N-WASP correlated with a reduced internalization of bacteria per macrophage, independently of the phagocytosis index. Furthermore, the downregulation of WASP levels accompanied those of N-WASP, at early but not at late time points, suggesting a closely regulatory mechanism among both family members, dependent on the time frame of the phagocytosis. Additionally, upregulating of miR-142-3p promoted the change in the protein levels of another predicted and confirmed target, the Cofilin2 protein, in a phagocytosis-independent fashion. Downregulation experiments promoted aberrant morphologic phenotypes in macrophages, similar to observed by others in PBMCs of humans with Wiskott Aldrich Syndrome, suggesting the strong involvement of miR-142-3p on the regulation of the actin machinery in macrophages. Altogether these results show for the first time that miRNAs are involved in the regulation of actin-mediated phagocytosis of pathogenic bacteria and that these are direct targets of Mycobacterium tuberculosis. Expression analysis of mouse macrophage cell line J774A.1 in response to infection with Mycobacterium smegmatis mc2155 EGFP. Three biological replicates each for uninfected and infected samples.

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Aging Impairs Macrophage Phagocytosis through Mitochondrial ROS-Induced Collagen Production

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