CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Abstract

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.pain | inflammation | cytokines | monocytes | macrophages

Pain regulation by non-neuronal cells and inflammation

“…In most cases, these cells produce pain through the release of pro-inflammatory mediators such as TNF and IL-1β(11), resulting in enhanced pain transduction and conduction via modulation of ion channels such as TRPA1, TRPV1 and Nav1.7-1.9(1, 2). Cell-specific depletion of proliferating monocytes and macrophages impairs the development of mechanical and thermal hypersensitivity caused by sterile incision and pathogens, in parallel with a decrement in IL-1β and other pro-algesic mediators at the site of inflammation(15). However, in a nerve injury model deletion of peripheral monocytes does not affect neuropathic pain development(16).…”

Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation

“…In mouse models of carrageenan-induced inflammatory pain [2] and neuropathic pain [3], neutrophils migrate to tissues where they sustain pain through production of cytokines and prostaglandin E 2 (PGE 2 ). In incisional wound injury, non-neutrophilic CD11b + myeloid cells (likely macrophages) are responsible for pain sensitization [4]. Mast cells also play key roles in sensitizing nociceptors.…”

Effects of local and spinal administrations of mu-opioids on postoperative pain in aged vs adult mice

“…The mechanisms of postoperative and inflammatory pain have similarities, as well as many notable differences [9]. For example, the wound healing process after surgery recruits a unique subset of inflammatory cells to the injury site, which is substantially different from a set of immune cells generated by CFA injection [16]. It also can be noted that mu-opioid induced thermal (but not mechanical) anti-nociception can be registered without the presence of inflammation, as soon as opioids are administrated spinally [36].…”