Aging is a myeloid-biased process, i.e., the differentiation of myeloid cells increases, while the lymphoid lineage declines. Cellular senescence increases the secretion of inflammatory mediators which skew hematopoiesis toward myeloid cell generation. Myeloid cell nuclear differentiation antigen (MNDA) is a type-1 interferon (IFN)-inducible factor which is mainly expressed in the cells of the granulocyte-monocyte lineage, especially it is enriched in M2 macrophages and myeloid-derived suppressor cells (MDSC). MNDA regulates gene expression in the cooperation with the IRF7, Sp1, and YY1 transcription factors. MNDA also inhibits the function of two antiapoptotic proteins, i.e., MCL1 and BCL2, thus promoting apoptotic clearance of myeloid cells during the resolution of inflammation. Moreover, MNDA can prevent excessive inflammation by inducing the polarization of M2 macrophages and enhancing the recruitment of MDSCs into inflamed tissues. Immunosuppressive cells not only inhibit inflammation but they can also promote senescence of immune and non-immune cells as well as triggering fibrosis and other age-related alterations. We propose a scenario where the accumulation of senescent cells with aging promotes a leakage of double-stranded DNA (dsDNA) from impaired mitochondria and nuclei thus activating cytoplasmic dsDNA sensors. Activation of cGAS-STING signaling generates the production of type-1 IFNs and thus MNDA may potentially enhance the myeloid-biased aging process and aggravate many age-related diseases. • MNDA is a type-1 interferon-inducible myeloid cell differentiation factor. • MNDA is a multifunctional regulator of the gene expression associated with myelopoiesis. • MNDA stimulates the polarization of M2 macrophages and the recruitment of MDSCs. • MNDA counteracts excessive inflammatory responses and promotes resolution. • MNDA promotes myeloid-biased inflammaging via cGAS-STING signaling.
Salminen et al. (Sun,) studied this question.