Production of MHCII‐expressing classical monocytes increases during aging in mice and humans

Abstract

Aging is associated with increased monocyte production and altered monocyte function. Classical monocytes are heterogenous and a shift in their subset composition may underlie some of their apparent functional changes during aging. We have previously shown that mouse granulocyte-monocyte progenitors (GMPs) produce "neutrophil-like" monocytes (NeuMo), whereas monocyte-dendritic cell progenitors (MDPs) produce monocyte-derived dendritic cell (moDC)-producing monocytes (DCMo). Here, we demonstrate that classical monocytes from the bone marrow of old male and female mice have higher expression of DCMo signature genes (H2-Aa, H2-Ab1, H2-Eb1, Cd74), and that more classical monocytes express MHCII and CD74 protein. Moreover, we show that bone marrow MDPs and classical monocytes from old mice yield more moDC. We also demonstrate higher expression of Aw112010 in old monocytes and that Aw112010 lncRNA activity regulates MHCII induction in macrophages, which suggests that elevated Aw112010 levels may underlie increased MHCII expression during monocyte aging. Finally, we show that classical monocyte

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide

“…Notably, interferon signaling can be triggered not only by mtDNA 2 , but can also induce the expression mtDNA- encoded MOTS-c ( Figure 3C and 3E ) 64 . Increased expression of genes involved in antigen presentation and interferon signaling with age has been observed in monocytes and macrophages in mice 122–126 . In fact, the antigen presentation genes H2-Aa, H2-Ab1, H2-Eb1, CD74, and AW112010 and interferon-related genes Irf7, Ifit2, Ifit3, Ifitm3 , and Ifi204 are consistently upregulated with age in our data and that of others ( Table S3 ) 122–125 , indicating a conserved effect of aging on monocytes/macrophages.…”

Murine GMP- and MDP-derived classical monocytes have distinct functions and fates

“…Of note, SLAMF7 + pro-inflammatory MF were shown to be IFNg-dependent and dominant in human patients with rheumatoid arthritis, COVID-19, or inflammatory bowel disease 71 . Finally, Goodridge and colleagues recently reported that MDP-Mo accumulate in aged mice, as assessed by transcriptional profiling and MHC-II surface expression 72,73 . Clearly, MDP-Mo require further in-depth study, including their unequivocal delineation from cDC and their precursors.…”

Aging of classical monocyte subsets

“…These observations suggested increased output by the MDP pathway, which yields moDC via DC-like monocytes (DCMo) [ 4 ]. We identified the DCMo cluster in our scRNAseq dataset, verified that MHCII gene ( H2-Aa , H2-Ab1 , H2-Eb1 ) and Cd74 expression was primarily restricted to this subset in both young and old mice, and attributed the more abundant transcripts in old monocytes to both increased expression among DCMo and a larger proportion of DCMo expressing detectable levels of these transcripts [ 5 ] (summarized in Figure 1B ). In contrast, MHCI gene ( H2-K1 , H2-Q7 ) and B2m expression increased in all classical monocyte clusters upon aging.…”

“…We previously demonstrated that classical monocytes in mouse bone marrow comprise multiple subsets that arise independently from granulocyte-monocyte progenitors (GMPs) or monocyte-dendritic cell progenitors (MDPs) [ 4 ] ( Figure 1A ). In our latest study [ 5 ], we evaluated how aging impacts classical monocyte heterogeneity and gene expression in both male and female mice.…”