An important role for prokineticin 2 in autoimmune CNS demyelination

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS often accompanied by neuronal loss. The small molecules prokineticins and their receptors are expressed in immune and neuronal cells. Prokineticin 2 (PK2), also known as Bv8, is involved in multiple biological functions including immune modulation. Here we identify PK2 as a critical mediator of experimental autoimmune encephalomyelitis (EAE), animal model of CNS autoimmunity mimicking MS. PK2 mRNA expression was upregulated in the spinal cord and lymph node cells (LNCs) of mice with chronic EAE compared with naïve mice. PK2 protein was expressed in CNS inflammatory infiltrates and was increased in sera of mice with EAE. In relapsing-remitting MS patients, transcripts for PK2 were significantly increased in PBMC compared with healthy subjects, and PK2 serum concentrations were significantly higher. PKRs antagonist prevented or treated established disease in both chronic and relapsing-remitting EAE, reduced CNS inflammation and demyelination, and decreased in LNCs the production of pro-inflammatory cytokines IL-17A and IFN-γ while increasing that of IL-10. PK2 in vitro increased the production of IL-17A and IFN-γ and reduced that of IL-10 in splenocytes activated against myelin antigen, and these effects were reversed by PKRs antagonist. These findings suggest that PK2 plays a crucial role in autoimmune CNS demyelination and might represent a novel target of treatment for this disease