IL-33/ST2 Signaling and Microglial Functional-State Transitions After Spinal Cord Injury: Direct Evidence and Mechanistic Hypotheses

Spinal cord injury (SCI) triggers a complex and evolving cascade of pathological events in which neuroinflammation and microenvironmental imbalance critically constrain repair. Among the cellular mediators, microglia exhibit remarkable functional plasticity, transitioning across diverse states that can either support tissue repair or exacerbate secondary damage. However, the mechanisms governing this dynamic reprogramming remain incompletely understood, limiting the development of effective immunomodulatory strategies. Recent evidence identifies the interleukin-33 (IL-33)/ST2 axis as an emerging, context-dependent regulator linking immune responses to neural repair. Rapidly released as an alarmin following injury, IL-33 modulates microglial function across spatiotemporal dimensions. Here, we propose a two-stage working model integrating direct evidence from SCI with extrapolated insights from broader central nervous system (CNS) pathologies. While acute IL-33 signaling is directly demonstrated in SCI models to limit early neuroinflammation and contain tissue damage, its putative role in driving a subsequent reparative microglial phenotype—encompassing metabolic adaptation and specialized phagocytic clearance—remains a hypothesis largely inferred from brain injury and neurodegenerative paradigms. Furthermore, we explore how IL-33 might modulate intercellular crosstalk with regulatory T cells and astrocytes, emphasizing that these downstream reparative mechanisms require definitive validation within the specific microenvironment of the injured spinal cord. In this Review, we synthesize current advances in the understanding of SCI pathology, microglial heterogeneity, and IL-33-mediated signaling. We highlight how IL-33 integrates inflammatory, metabolic, and transcriptional programs to drive microglial functional reprogramming, and we evaluate emerging therapeutic strategies targeting this pathway. Despite promising preclinical findings, challenges remain in optimizing delivery, timing, and safety. A deeper understanding of the IL-33/ST2 axis and its context-dependent effects may enable precise immunomodulation, offering new avenues to overcome barriers to regeneration and improve functional recovery after SCI.