From microglial activation to neurovascular remodeling: Chitinases as integrative mediators in ischemic stroke – A narrative review

Abstract:

Ischemic stroke is characterized by a complex interplay between neuroinflammation, oxidative stress, and vascular dysfunction, ultimately leading to disruption of the neurovascular unit and impaired tissue recovery. While microglial activation is a central driver of postischemic inflammation, increasing evidence indicates that this response is regulated by interconnected molecular and cellular mechanisms rather than isolated pathways. Among emerging modulators, chitinases and chitinase-like proteins have gained attention for their involvement in innate immune activation and tissue remodeling beyond their traditional role as biomarkers. In particular, Chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1) are upregulated in response to ischemic injury and are produced by activated microglia, macrophages, and vascular cells. These molecules have been associated with inflammatory signaling, extracellular matrix (ECM) turnover, and neurovascular responses, including angiogenesis and blood–brain barrier modulation. Experimental evidence from inflammatory and neurodegenerative conditions further suggests that CHI3L1 may interact with receptor-associated signaling pathways linked to inflammatory regulation and tissue remodeling, whereas CHIT1 appears to be more closely associated with innate immune activation and phagocytic responses. In this narrative review, we provide an overview of the biological functions of chitinases in the central nervous system and discuss their potential involvement in ischemic stroke. We examine their association with microglial activation, neuroinflammation, neurovascular remodeling, ECM dynamics, and immune-metabolic crosstalk, highlighting both experimental and clinical evidence. We also critically address current limitations, including the predominance of associative data, the lack of stroke-specific mechanistic studies, and the heterogeneity of available clinical evidence. Overall, current findings suggest that chitinases may participate in coordinated inflammatory and neurovascular responses within the ischemic microenvironment rather than acting solely as passive inflammatory markers. However, most available evidence remains associative, and direct mechanistic studies in ischemic stroke models are still limited. Therefore, this review should be interpreted as a hypothesis-generating framework that integrates current evidence while identifying key directions for future mechanistic and translational investigation.