AUTHOR=Saraiva-Santos Telma , Zaninelli Tiago H. , Manchope Marília F. , Andrade Ketlem C. , Ferraz Camila R. , Bertozzi Mariana M. , Artero Nayara A. , Franciosi Anelise , Badaro-Garcia Stephanie , Staurengo-Ferrari Larissa , Borghi Sergio M. , Ceravolo Graziela S. , Andrello Avacir Casanova , Zanoveli Janaína Menezes , Rogers Michael S. , Casagrande Rubia , Pinho-Ribeiro Felipe A. , Verri Waldiceu A. 

TITLE=Therapeutic activity of lipoxin A4 in TiO2-induced arthritis in mice: NF-κB and Nrf2 in synovial fluid leukocytes and neuronal TRPV1 mechanisms

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.949407

DOI=10.3389/fimmu.2023.949407

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Lipoxin A4 (LXA<sub>4</sub>) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO<sub>2</sub>) arthritis, a model of prosthesis-induced joint inflammation and pain.</p></sec><sec><title>Methods</title><p>Mice were stimulated with TiO<sub>2</sub> (3mg) in the knee joint followed by LXA<sub>4</sub> (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA<sub>4</sub><italic>in vivo</italic>.</p></sec><sec><title>Results</title><p>LXA<sub>4</sub> reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA<sub>4</sub> reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA<sub>4</sub> improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)<sup>+</sup> DRG nociceptive neurons upon TiO<sub>2</sub> inflammation. LXA<sub>4</sub> reduced TiO<sub>2</sub>‐induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA<sub>4</sub> down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons.</p></sec><sec><title>Conclusion</title><p>LXA<sub>4</sub> might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.</p></sec>