Cathelicidin-related
antimicrobial peptide (
CRAMP) is an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory activities; however, its role in neuroinflammatory responses and related diseases is not clearly understood. In particular, the expression of
CRAMP and its functional role has not been previously studied in
experimental autoimmune encephalomyelitis (EAE) or
multiple sclerosis (MS). Here, we investigated the role of
CRAMP in
neuroinflammation, using an EAE mouse model of MS and postmortem patient tissues. We found that the
CRAMP expression was increased in the spinal cords of EAE-induced mice. Immunofluorescence analysis revealed that
CRAMP is mainly induced in reactive astrocytes in the inflamed spinal cord of EAE mice. A similar pattern of the LL-37 (human
CRAMP) expression was observed in the brain and spinal cord tissues of patients with MS. An
intrathecal injection of the
CRAMP peptide in EAE mice accelerated the onset of symptoms and increased disease severity with augmented expression of inflammatory mediators, glial activation, infiltration of inflammatory cells, and
demyelination. In addition,
shRNA-mediated knockdown of
Cramp in the spinal cord resulted in a milder disease course with less
inflammation in EAE mice. We identified FPR2 on microglia as a
CRAMP receptor and demonstrated that
CRAMP potentiates IFN-γ-induced microglial activation via the STAT3 pathway. Taken together, our findings suggest that
CRAMP is a novel mediator of astrocyte-microglia interactions in neuroinflammatory conditions such as EAE. Thus,
CRAMP could be exploited as a
biomarker or therapeutic target for the diagnosis or treatment of MS.