AUTHOR=Dai Xiaolong , Li Lianlian , Yan Xinrong , Fan Qianqian , Wang Ruizhen , Zhang Wenhao , Chen Weiwei , Liu Yang , Meng Jianghui , Wang Jiafu 

TITLE=Myeloid Vamp3 deletion attenuates CFA-induced inflammation and pain in mice via ameliorating macrophage infiltration and inflammatory cytokine production

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1239592

DOI=10.3389/fimmu.2023.1239592

ISSN=1664-3224

ABSTRACT=<p>Persistent inflammation and associated pain significantly impact individuals’ quality of life, posing substantial healthcare challenges. Proinflammatory cytokines, released by activated macrophages, play crucial roles in the development of chronic inflammatory conditions such as rheumatoid arthritis. To identify and evaluate potential therapeutic interventions targeting this process for mitigating inflammation and pain, we created myeloid cell-specific knockout of <italic>Vamp3</italic> (vesicle-associated membrane protein 3) mice (<italic>Vamp3</italic><sup>Δmyel</sup>) by crossing <italic>LysM-Cre</italic> mice with newly engineered <italic>Vamp3<sup>flox/flox</sup></italic> mice. Bone marrow-derived macrophages and peritoneal resident macrophages from <italic>Vamp3</italic><sup>Δmyel</sup> mice exhibited a significant reduction in TNF-α and IL-6 release compared to control mice. Moreover, Vamp3 deficiency led to decreased paw edema and ankle joint swelling induced by intraplantar injection of complete Freund’s adjuvant (CFA). Furthermore, Vamp3 depletion also mitigated CFA-induced mechanical allodynia and thermal hyperalgesia. Mechanistically, Vamp3 loss ameliorated the infiltration of macrophages in peripheral sites of the hind paw and resulted in reduced levels of TNF-α and IL-6 in the CFA-injected paw and serum. RT-qPCR analysis demonstrated downregulation of various inflammation-associated genes, including <italic>TNF-α</italic>, <italic>IL-6</italic>, <italic>IL-1β</italic>, <italic>CXCL11</italic>, <italic>TIMP-1</italic>, <italic>COX-2</italic>, <italic>CD68</italic>, and <italic>CD54</italic> in the injected paw at the test day 14 following CFA administration. These findings highlight the novel role of Vamp3 in regulating inflammatory responses and suggest it as a potential therapeutic target for the development of novel Vamp-inactivating therapeutics, with potential applications in the management of inflammatory diseases.</p>