title: Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain.
abstract: 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 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.
authors: Department of Pharmacology, Wakayama Medical University, Wakayama, Japan Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
authors: Norikazu
authors: N
authors: Kiguchi
authors: Yuka
authors: Y
authors: Kobayashi
authors: Fumihiro
authors: F
authors: Saika
authors: Haruka
authors: H
authors: Sakaguchi
authors: Takehiko
authors: T
authors: Maeda
authors: Shiroh
authors: S
authors: Kishioka
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D015847:Interleukin-4 / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D012585:Sciatica / Q000150:complications* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D015847:Interleukin-4; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
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