The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of “inflammaging” has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.

Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS. Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFβ: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.