D-Dopachrome Tautomerase-Driven Astrocytic CCL7 Aggravates Neuropathology by Recruitment of Microglia Following...

Chemokines-induced infiltration of leukocytes into damaged tissues following spinal cord injury (SCI) profoundly influences the neuropathology and neurological functional recovery. Astrocytes are among the primary cell types rapidly activated to produce various chemokines immediately after SCI. However, the molecular mechanisms regulating the expression of astrocytic chemokines, particularly the inflammation-related chemokine C-C motif ligand 7 (CCL7), remain elusive. D-dopachrome tautomerase (D-DT, also known as MIF-2), a member of the macrophage migration inhibitory factor (MIF) family, has been shown to deteriorate the inflammatory milieu and worsen neurological outcomes following SCI. In this study, CCL7 was dramatically induced in astrocytes following SCI and contributed to the accumulation of microglia/macrophages at lesion sites. In vitro experiments demonstrated that astrocyte-derived CCL7 significantly promoted microglia/macrophages migration through coupling with chemokine C-C motif receptor 2 (CCR2). Blocking of CCL7 with a neutralizing antibody or administering a CCR2 inhibitor substantially ameliorated tissue damage and promoted locomotor recovery. Further mechanistic investigation revealed that the D-DT/CD74 axis enhanced astrocytic CCL7 production by activating the MAPKs/NF-κB and IL-6/STAT3 signaling pathways. Treatment with the D-DT pharmacological inhibitor 4-CPPC reduced astrocytic CCL7 production and consequently limited microglia/macrophages accumulation at lesion sites after SCI. These findings uncover a novel regulatory pathway for astrocyte-derived CCL7 production and highlight its detrimental role in neurological recovery, which might provide new clues for clinical treatment of neuroinflammation after SCI.