Abstract Body: Background: Stroke remains a leading cause of death globally, with significant sex differences in post-stroke outcomes. Additionally, post-stroke infections and sepsis are linked to differences in innate immune responses. The glycosidase, Chitotriosidase 1 (CHIT1), has emerged as an important regulator of innate immunity and lower levels of CHIT1 and chitinases-like proteins are associated with disease severity and progression including multiple sclerosis. However, whether CHIT1 plays a role in the response to acute ischemic stroke is unknown.
Hypothesis: We hypothesized that sex-specific alterations in pro-inflammatory factors, including CHIT1, contribute to differential patterns of phagocytosis and post-stroke outcomes.
Methods: We examined the effects of acute ischemic stroke (AIS) in older men and women, specifically circulatory cytokine production, circulatory phagocytosis assessment utilizing fluorescent bead engulfment assay, and if these correlated with post-stroke complications in peripheral blood mononuclear cells (PBMCs). We examined relationships with stroke severity, as measured by the NIH Stroke Scale (NIHSS) in patients with a NIHSS>6.
Results: Our findings reveal that older women exhibit lower levels of CHIT1 activity correlating with poorer survival outcomes in AIS (p<0.05, n=7-11/grp) compared to men (ns, n=21-22/grp). Female presented a robust phagocytic capability and CHIT1 depression on peripheral monocytes (p<0.05, n=7-11/grp). This effect is not observed in men, who exhibit greater phagocytic capacity after 1 day after stroke (p<0.01, n=21-22/grp) measured by bead uptake assay using flow cytometry. Variations in CHIT1 levels in PBMCs correlated with stroke severity and infection risk, underscoring its potential role in sex-dependent outcomes.
Conclusion: Our data suggests that peripheral reduction of CHIT1 levels impairs phagocytosis and increases susceptibility to infections as a risk factor for poorer stroke outcomes. CHIT1 appears to be a novel mediator of sex differences in post-stroke immune suppression. Targeting the anti-fungal response protein CHIT1 could help normalize phagocytic responses in older women, potentially reducing infection rates and improving post-stroke outcomes. Further research into CHIT1's interaction with pathogen-associated molecular patterns could provide new therapeutic strategies for stroke management.