Context-dependent CCL2-CCR2 signaling drives distinct immune infiltration programs in traumatic and autoimmune CNS disorders.

Spinal cord injury (SCI) and multiple sclerosis (MS) are distinct central nervous system (CNS) disorders-representing acute traumatic injury and chronic autoimmunity, respectively-yet both feature peripheral immune cell infiltration into the CNS. Here, using human cerebrospinal fluid (CSF) ELISA, public single-cell RNA sequencing datasets, and Ccr2-deficient mouse models of SCI and experimental autoimmune encephalomyelitis (EAE), we conducted a parallel multi-level analysis of the CCL2-CCR2 signaling axis. We found fundamentally distinct temporal dynamics of CCL2: a transient surge during acute SCI, but no significant fluctuation across MS disease stages. Single-cell analysis revealed divergent immune infiltration programs: SCI was dominated by rapid, transient innate immune cell recruitment, while EAE showed sustained accumulation of CD4+ T cells and monocytes. Consistently, CCR2 was acutely induced in infiltrating macrophages in SCI and declined rapidly, but remained persistently elevated in monocytes and CD4+ T cells in EAE. Notably, CCR2 deficiency triggered context-dependent immune remodeling: it reduced macrophage infiltration in SCI with compensatory CD4+ T cell expansion, whereas in EAE it broadly suppressed both innate and adaptive immune infiltration and conferred near-complete disease protection. Collectively, the CCL2-CCR2 axis functions as a context-dependent regulator of immune infiltration, orchestrating transient innate responses in acute injury and sustained adaptive immunity in chronic autoimmunity. These findings highlight the need for disease- and phase-specific targeting of chemokine pathways for precision immunomodulation in CNS disorders.