Heterogeneity in pericyte inflammatory responses across age and species highlight the importance of human cell models

Abstract

Pericytes in the central nervous system are essential for maintaining blood-brain barrier function, regulating blood flow, modulating immune responses, and interacting closely with surrounding cells of the neurovascular unit to support brain homeostasis. Increasing evidence has highlighted their involvement in age-related neuroinflammation, where their dysfunction may contribute to sustained inflammatory states associated with neurodegenerative disorders. Here, we compared inflammatory responses to lipopolysaccharide (LPS) in primary cerebral pericytes from neonatal and adult mice and adult humans. Our findings indicate that neonatal mouse pericytes display heightened inflammatory activation, with elevated levels of ICAM-1 and several cytokines, compared to adult mouse pericytes reflecting a more reactive phenotype. In contrast, adult mouse pericytes exhibited a significantly reduced cytokine release profile, suggesting lower responsiveness. Notably, while cytokine secretion patterns in adult human pericytes, in part, mirrored those in neonatal mouse pericytes, nitric oxide production, which was observed in mouse pericytes, was absent in the human cells. These results underscore species- and age-dependent variations in cellular behavior, emphasizing the importance of utilizing human brain cell systems when conducting research on neuroinflammation. Understanding these distinctions is vital for designing accurate studies and developing targeted therapies for neuroinflammatory conditions.