Cytokine-regulated neutrophil recruitment is required for brain but not spinal cord inflammation during EAE

Abstract

Multiple sclerosis is an autoimmune disease characterized by inflammatory lesions throughout the central nervous system (CNS). The location of lesions is a critical determinant of clinical signs but varies among patients. While both IFN-gamma and IL-17 signaling influence lesion location in mouse models of MS, the mechanisms underlying their activities are unknown. We show that IL-17 promotes, but IFN-gamma inhibits, ELR+ chemokine-mediated neutrophil recruitment to the brain, which is required for parenchymal tissue damage in the brain. In contrast, IFN-gamma promotes rather than inhibits ELR+ chemokine expression and neutrophil recruitment in the spinal cord. Surprisingly, tissue injury in the spinal cord does not exhibit the same dependence on neutrophils that was observed for the brain. Thus, the brain and spinal cord exhibit distinct sensitivities to cellular mediators of tissue damage, and IL-17 and IFN-gamma differentially regulate recruitment of these mediators to each microenvironment. These data suggest that the specific region targeted by inflammatory lesions in individual patients may predict their response to therapies that neutralize cytokine activity.