Fibroblast–immune crosstalk in central nervous system injury and repair: Spatiotemporal control of barrier restoration, inflammation resolution and fibrotic scarring

Abstract

Central nervous system repair after injury is increasingly understood as a spatially and temporally organized process involving vascular disruption, immune-cell recruitment, extracellular matrix remodeling and reconstruction of glial–stromal borders. Within this process, central nervous system fibroblasts are not merely matrix-producing scar cells, but injury-responsive stromal organizers positioned at key neuroimmune interfaces, including the meninges, perivascular spaces and choroid plexus. Recent single-cell, spatial and lineage-resolved studies indicate that anatomically distinct fibroblast populations undergo phase-specific state transitions after traumatic brain injury, stroke, and spinal cord injury. During the acute phase, activated fibroblasts and myofibroblast-like states contribute to lesion containment, barrier restoration and protection of surrounding parenchyma. In the subacute and chronic phases, fibroblasts interact dynamically with neutrophils, microglia, macrophages, lymphocytes and innate lymphoid cells to shape immune-cell positioning, inflammatory resolution, vascular repair and, when unresolved, persistent fibrotic scarring. This review synthesizes emerging evidence on fibroblast–immune crosstalk in central nervous system injury, with particular emphasis on the unresolved origins of injury-responsive stromal cells, lesion-topology-dependent fibroblast recruitment, C–X–C motif chemokine ligand 12-mediated lymphocyte organization, choroid plexus fibroblast–group 2 innate lymphoid cell niches, and fibroblast contributions to blood–brain barrier and vascular repair. Rather than framing fibrotic scars as uniformly detrimental, we propose that central nervous system fibrosis reflects context-dependent fibroblast states that can be either reparative or maladaptive depending on timing, anatomical niche and immune milieu. Therapeutic strategies should therefore avoid indiscriminate fibroblast depletion and instead aim to preserve early protective functions while selectively modulating chronic fibroblast–immune circuits that sustain inflammation and inhibit regeneration.