Pro-inflammatory effects of all-trans retinoic acid in experimental acute inflammation - insights into eosinophil and neutrophil dynamics.

Abstract

Context: All-trans retinoic acid (ATRA), a metabolite of vitamin A, regulates embryogenesis, regeneration, hematopoiesis, differentiation, and apoptosis. It also exerts immunomodulatory effects and is used in inflammatory disease models.

Objective: This study aimed to investigate the paradoxical pro-inflammatory effects of ATRA on eosinophil and neutrophil recruitment and activation.

Materials and methods: We used thioglycolate- and zymosan-induced peritonitis models in mice to evaluate leukocyte recruitment following ATRA treatment. The roles of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), and the 5-lipoxygenase (5-LO) pathway were assessed using genetically deficient mice and pharmacological inhibitors.

Results and discussion: ATRA increased total leukocyte, eosinophil, and neutrophil counts in peritoneal exudates, enhancing the response to both thioglycolate and zymosan. The effects were microenvironment-dependent and likely mediated by local release of pro-inflammatory cytokines and chemokines. iNOS was required for eosinophil recruitment, while TNF contributed to both eosinophil and neutrophil recruitment. The 5-LO pathway was essential for eosinophil involvement. These findings suggest that ATRA can paradoxically enhance inflammation by modulating innate immune cell responses.

Conclusions: ATRA promotes inflammation through iNOS, TNF, and 5-LO-dependent pathways, revealing complex mechanisms of immune modulation with potential relevance for inflammatory disease management.