Abstract Body: Introduction: Loneliness and social isolation (SI) are associated with both an increased risk of stroke and poor outcomes after stroke. However, the biological mechanisms that mediate how social factors affect stroke recovery are unknown. We hypothesized that the detrimental consequences of post-stroke SI result from differential miRNA expression that impacts neuroinflammation.
Methods: To investigate the negative effects of post-stroke SI on brain miRNA profiles, aged (18–20 months) C57BL/6 male mice were utilized. Mice were randomly assigned to pair housing (PH) or single housing (SI) after middle cerebral artery occlusion (MCAO). We investigated the abundance of miRNA transcripts in isolated peripheral blood mononuclear cells (PBMCs) samples of lonely and socially integrated patients 24 hours after stroke (n = 140) using the UCLA loneliness and Lubben social interaction scales.
Results: MiR-10a-5p, identified as a top differentially expressed target across mice and human-isolated stroke patients, was found to be a crucial node in the pool of miRNAs that interacted with the largest group of miRNAs for post-stroke at SI D4 in mice. At post-stroke, SI D4, significant microglial activation and suppression of cytokine production were observed as assessed by the median fluorescence intensity (MFI) of purinergic receptor P2Y12 (P2RY12), interleukin (IL)-4, IL-1β, and tumor necrosis factor (TNF)α, respectively, in microglial cells in the brain. The MFI of P2RY12 was significantly downregulated in post-stroke SI mice at D4 (n = 7-8/grp, *p<0.05) compared to PH mice. MFI of IL-4, IL-1β, and TNFα were significantly downregulated in post-stroke SI mice at D4 (n = 8–11/grp, *p<0.05, **p<0.01) compared to PH mice. Analysis of circulatory miRNA profiles revealed significantly altered sex-specific patterns of miRNAs (i.e., miR-24-3p, miR-143-3p, miR-223-5p, miR-192-5p, miR-331-3p, and miR-328-3p) (n = 40-50/grp, FDR adjusted *p<0.05) in isolated stroke patients.
Conclusions: These findings validate our hypothesis that post-stroke SI exacerbates microglial activation, leading to differential expression of miRNAs that regulate microglial pathways. Further, alterations of sex-specific miRNA profiles in isolated post-stroke patients suggest its potential as a biomarker. Taken together, utilizing sex-specific miRNA-based therapies to restore miRNA profiles in the brain may be able to alleviate the detrimental impact of post-stroke SI on chronic depressive-like phenotypes.