Ghasemlou Nader, Chiu Isaac M, Julien Jean-Pierre, Woolf Clifford J
F. M. Kirby Neurobiology Center, Boston Children's Hospital & Harvard Medical School, Boston, MA 02115;
F. M. Kirby Neurobiology Center, Boston Children's Hospital & Harvard Medical School, Boston, MA 02115; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):E6808-17. doi: 10.1073/pnas.1501372112. Epub 2015 Nov 23.
Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant- and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G(+)CD11b(+) neutrophils and T-cell receptor (TCR) β(+) T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b(+)Ly6G(-) myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2(+)Ly6C(hi)) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b(+)Ly6G(-) myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.
慢性免疫疾病、致病性感染和组织损伤导致的炎症部位疼痛超敏是一种常见的医学状况。然而，先天性和适应性免疫系统在炎症过程中对疼痛产生的具体作用尚未得到系统阐明。因此，我们着手在两种广泛使用的炎症性疼痛临床前模型中表征细胞和分子免疫反应：（i）足底注射完全弗氏佐剂（CFA）作为基于佐剂和病原体的炎症模型，以及（ii）足底切开伤口作为基于组织损伤的炎症模型。我们的研究结果揭示了这两种模型在免疫细胞募集和激活状态、细胞因子产生以及疼痛的时间模式上的差异，CFA导致一种无法消退的肉芽肿性炎症反应，而组织切开诱导炎症和疼痛反应消退。这些发现突出了切开伤口模型与CFA模型相比的显著差异和潜在临床相关性。通过使用各种细胞清除策略，我们发现，虽然淋巴细胞抗原6复合体基因座G（Ly）6G（+）CD11b（+）中性粒细胞和T细胞受体（TCR）β（+）T细胞在两种模型中均对热或机械性疼痛超敏的发展无贡献，但增殖的CD11b（+）Ly6G（-）髓样细胞在切开疼痛期间对机械性超敏是必需的，在较小程度上对CFA诱导的炎症也是必需的。然而，炎性（CCR2（+）Ly6C（高））单核细胞对这些效应无作用。增殖的CD11b（+）Ly6G（-）髓样细胞群体促成机械性炎性疼痛这一发现为伤口炎症中该疼痛的治疗提供了一个潜在的细胞靶点。
