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

Front Immunol. 2023 Jun 14:14:949407. doi: 10.3389/fimmu.2023.949407. eCollection 2023.

Abstract

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain.

Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (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 LXA4 in vivo.

Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 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)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons.

Conclusion: LXA4 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.

Keywords: ALX/FPR2; ROS; TRPV1; TiO2; inflammation; lipoxin A4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis*
  • Inflammation
  • Lipoxins* / pharmacology
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-kappa B
  • Synovial Fluid
  • TRPV Cation Channels / genetics

Substances

  • NF-kappa B
  • titanium dioxide
  • NF-E2-Related Factor 2
  • Lipoxins
  • TRPV1 protein, mouse
  • TRPV Cation Channels

Grants and funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; #309633/2021-4; #307852/2019-9; #307689/2022-0; #405027/2021-4; #427946/2018-2); Financiadora de Estudos e Projetos-Apoio à Infraestrutura (FINEP CT-INFRA); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; finance code 001); Programa de Pesquisa para o Sistema Único de Saúde (PPSUS) grant supported by Ministério da Ciência, Tecnologia e Inovação (MCTI), Secretaria da Saúde do Estado do Paraná (SESA-PR), and Parana State Government (Brazil) (agreements #041/2017); and Programa de Apoio a Grupos de Excelência (PRONEX) grant supported by SETI/Fundação Araucária and MCTI/CNPq, and Governo do Estado do Paraná (agreement #014/2017).