Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain.

There is increasing evidence that inflammatory (M1-polarized) macrophages drive the nonresolving neuroinflammation that causes neuropathic pain after nerve injury. As interleukin-4 (IL-4) promotes the suppressive (M2-polarized) state in macrophages, we examined whether exploiting an IL-4-mediated pathway could ameliorate M1 macrophage-dependent neuropathic pain. The mRNA and protein expression of IL-4 receptor a chain (IL-4Ra) were upregulated in accumulating F4/80 1 macrophages in injured sciatic nerve (SCN). Inmouse macrophage cell lineJ774A.1,IL-4 downregulated the mRNA expressionof M1macrophage-specific molecules (IL-1b, CC chemokine ligand 3, and CD86) normally provoked by lipopolysaccharide, while increasing the mRNA expression of M2 macrophage-specific molecules (arginase-1, IL-10, and CD206) through a STAT6-mediated pathway. In ex vivo SCNculture,M1moleculeswerehighlyexpressedintheinjuredSCNonday7afterpartialSCNligation(PSL)butweredecreasedby IL-4 treatment. In contrast, M2 molecules were upregulated by IL-4. IL-4 also increased phosphorylated STAT6 (pSTAT6) expression and shifted IL-1b 1 M1 macrophages toward a CD206 1 M2 phenotype. Perineural administration of IL-4 in mice subject toPSLameliorateddevelopmentandmaintenanceoftactileallodyniaandthermalhyperalgesia.TheseeffectsofIL-4werebasedon thatIL-4treatment increasedtheproportions ofpSTAT6 1 andCD206 1 macrophagesininjuredSCNonday14afterPSL.Wefound that neuropathic pain can be ameliorated by IL-4 treatment, which exerts its therapeutic effect on accumulating macrophages through a STAT6-dependent pathway. A shift in macrophage phenotype from the inflammatory to the suppressive phenotype, driven by IL-4R signaling, may have benefits in the treatment of neuropathic pain.