Activation of proresolving macrophages in dorsal root ganglia attenuates persistent arthritis pain

• 成果类型: Article
• 署名作者: Oggero, Silvia; Voisin, Mathieu - Benoit; Picco, Francesca; Huerta, Miguel A.; Cecconello, Chiara; Burgoyne, Thomas; Perretti, Mauro; Malcangio, Marzia
• 署名单位: University of London; King's College London; University of London; Queen Mary University London; University of Granada; University of London; University College London; Royal Brompton Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13836
• DOI: 10.1073/pnas.2416343122
• 发表日期: 2025-03-18
• 关键词: lipid mediators; apoptotic neutrophils; RESOLUTION; efferocytosis; mechanisms

摘要

Pain independent of disease activity is frequently reported by rheumatoid arthritis patients and remains undertreated. Preclinical evidence suggests that imbalance of neuroimmune proresolving interactions within dorsal root ganglia (DRG) rather than at the site of inflammation plays mechanistic roles in persistent arthritis pain. Here, we inhibited production of proresolving lipid mediators by silencing 12/15-lipoxygenase expression in CX3CR1+ monocyte/macrophages conditional knockout (cKO) mice. In an arthritis model, hind paw mechanical hypersensitivity is exacerbated in male and female cKO mice in association with DRG infiltration of neutrophils, which migrate in response to leukotriene B4 released by macrophages through 5-lipoxygenase conversion of arachidonic acid provided by neuron-derived vesicles. Neutrophils apoptosis promotes primary macrophage efferocytosis which is defective in cKO macrophages. In wild-type (WT) and cKO mice, intrathecal injection of MerTK activating antibody, attenuates persistent hypersensitivity and polarizes DRG macrophages toward a proresolving phenotype with production of antinociceptive lipoxin A4. Thus, we delineate a neuron-macrophage-neutrophil bidirectional circuit that can be exploited to reduce persistent arthritis pain.