Neuroimmune responses in neonatal hypoxic-ischemic encephalopathy: cellular roles, crosstalk, and therapeutic opportunities.

Neonatal hypoxic-ischemic encephalopathy (HIE) is traditionally viewed as a consequence of acute oxygen and blood flow deprivation followed by excitotoxicity, oxidative stress, and neuronal death. However, growing evidence indicates that HIE is also a dynamic neuroimmune disorder in which immune cells actively shape injury progression, tissue remodeling, and long-term neurodevelopmental outcome. Among these cells, microglia function as the central immune hub of the injured neonatal brain, rapidly responding to damage signals and interacting with neurons, myeloid cells, and adaptive immune components. Recent studies further show that microglial activation is not uniformly detrimental, but depends on timing, phenotype, and signaling context. In parallel, phagocytes and broader myeloid networks amplify neuroinflammation through transcriptional programs such as IRF5, while regulatory T cells contribute to outcome heterogeneity and sexual dimorphism. These findings highlight that immune crosstalk in neonatal HIE is dynamic, phase-dependent, and developmentally specific. Therapeutically, the field is moving beyond therapeutic hypothermia alone toward pathway-defined immunomodulation, extracellular vesicle- and mesenchymal stromal cell-based approaches, and combination strategies that reshape the immune microenvironment. This review summarizes the roles of immune cells in neonatal HIE, emphasizes the importance of cellular crosstalk and temporal immune-state transitions, and discusses emerging opportunities for precision neuroimmune targeting.