Beyond the usual suspects: rethinking post-stroke immunosuppression.

Ischemic stroke extends far beyond the hyperacute vascular event. In addition to the immediate ischemic injury, patients frequently develop systemic complications that significantly influence outcome. Among these, a biphasic immune response has emerged as a central feature: an early inflammatory reaction followed by a state of peripheral immunosuppression. This immunosuppressive phase has been consistently associated with increased susceptibility to post-stroke infections, particularly pneumonia, thereby contributing to morbidity and mortality. Multiple mechanisms have been implicated in the development of stroke-induced immunosuppression, including activation of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis, the release of damage-associated molecular patterns (DAMPs), reprogramming of bone marrow hematopoiesis, and peripheral neutrophil activation with downstream effects on lymphocyte survival. While these pathways are often studied in isolation, accumulating evidence suggests that they may interact within a coordinated neuroimmune network. In this review, we not only summarize the current understanding of the mechanisms underlying post-stroke immunosuppression but also explore how these processes may converge and influence one another. Finally, we discuss the unresolved question of whether this immunosuppressive state represents an adaptive response aimed at protecting the injured brain or a maladaptive bystander consequence of disrupted neuroimmune homeostasis.