• Norikazu Kiguchi, Yuka Kobayashi, Fumihiro Saika, Haruka Sakaguchi, Takehiko Maeda, and Shiroh Kishioka.
• aDepartment of Pharmacology, Wakayama Medical University, Wakayama, Japan bDepartment of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
• Pain. 2015 Apr 1;156(4):684-93.

AbstractThere 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 α chain (IL-4Rα) were upregulated in accumulating F4/80 macrophages in injured sciatic nerve (SCN). In mouse macrophage cell line J774A.1, IL-4 downregulated the mRNA expression of M1 macrophage-specific molecules (IL-1β, 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 SCN culture, M1 molecules were highly expressed in the injured SCN on day 7 after partial SCN ligation (PSL) but were decreased by IL-4 treatment. In contrast, M2 molecules were upregulated by IL-4. IL-4 also increased phosphorylated STAT6 (pSTAT6) expression and shifted IL-1β M1 macrophages toward a CD206 M2 phenotype. Perineural administration of IL-4 in mice subject to PSL ameliorated development and maintenance of tactile allodynia and thermal hyperalgesia. These effects of IL-4 were based on that IL-4 treatment increased the proportions of pSTAT6 and CD206 macrophages in injured SCN on day 14 after PSL. We found 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.

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