期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：E6808-E6817
DOI：10.1073/pnas.1501372112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceInflammatory mediators can activate and sensitize nociceptors, specialized high-threshold nerve fibers that relay noxious signals to the spinal cord and brain to initiate pain. However, the contribution of specific immune cell types to pain in animal models of inflammation remains largely unknown. We therefore characterized the immune response in two widely used preclinical models of inflammatory pain: intraplantar injection of complete Freunds adjuvant and plantar incisional wound. Cell-depletion strategies investigated the contribution of neutrophils, myeloid cells (including monocytes and macrophages), and T cells to pain behavior outcomes. Our results show that these two models induced quite different inflammatory processes and that targeted elimination of a subpopulation of nonneutrophil myeloid cells blocked development of mechanical hypersensitivity following incisional wounds. 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 Freunds 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) {beta}+ 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+Ly6Chi) 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.
