Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain

• Published in: Pain (Amsterdam) Vol. 156; no. 4; pp. 684 - 693
• Main Authors: Kiguchi, Norikazu, Kobayashi, Yuka, Saika, Fumihiro, Sakaguchi, Haruka, Maeda, Takehiko, Kishioka, Shiroh
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Animals; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Cell Polarity - drug effects; Cells, Cultured; Cytokines - metabolism; Disease Models, Animal; Gene Expression Regulation - drug effects; Humans; Hyperalgesia - physiopathology; Inflammation - drug therapy; Inflammation - etiology; Inflammation - pathology; Interleukin-4 - therapeutic use; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred ICR; Pain Measurement; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Sciatica - complications; Sciatica - pathology; Signal Transduction - drug effects; STAT6 Transcription Factor - metabolism; Up-Regulation - drug effects
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1097/j.pain.0000000000000097

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.