BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Nutritional Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1609763
This article is part of the Research TopicImmunomodulation by Vitamins: Mechanistic insights and clinical translationView all articles
RETINOIC ACID DIFFERENTLY MODULATES NOD1/NOD2-MEDIATED INFLAMMATORY RESPONSES IN HUMAN MACROPHAGE SUBSETS
Provisionally accepted
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Macrophages are indispensable in homeostasis and innate immune responses in multiple tissues, while their polarization and functional characteristics are determined by the activating stimuli and their tissue microenvironment. The vitamin A derivative retinoic acid shows inhomogeneous distribution among the tissues and has an important modulatory role in inflammatory responses. However, its effects on the cytokine secretion induced by the cytosolic pattern-recognition receptors NOD1 and NOD2 are unclear.In our study, we used human monocyte-derived macrophages differentiated in the presence of GM-CSF or M-CSF to generate inflammation inducing (GM-M ) or inflammation resolving (M-M ) cells, respectively. We activated the cells with either a NOD1-or NOD2 specific agonist and, using ELISA, we determined the pattern and dynamics of cytokines secreted by the macrophage subpopulations. Furthermore, we studied the effect of all-trans retinoic acid (ATRA) pre-treatment on the NOD1-and NOD2-induced cytokine release. Our comparative analysis shows subpopulation-characteristic pattern of cytokine secretion, as GM-M produce significantly higher pro-inflammatory IL-6, IL-8, TNF- and IL-1, while M-M secret higher anti-inflammatory IL-10. However, IL-18 and IFNsecretion was comparable between the M subpopulations. We also show for the first time that ATRA has marked impact on cytokine secretion triggered by NOD1 and NOD2. Importantly however, the ATRA-induced changes of cytokine secretion follow opposite tendency in two M subpopulations. In conclusion, these results show that NOD1/NOD2-induced cytokine secretion by macrophage subsets is highly context-dependent and our results highlight the importance of the retinoic acid content of the local tissue environment in shaping macrophage function in health and disease.
Keywords: Retinoic acid, NOD1, Nod2, NOD-like receptor, Vitamin A, Inflammation, macrophage, cytokine
Received: 10 Apr 2025; Accepted: 16 Jun 2025.
Copyright: © 2025 Ahmad, Alatshan, Bíró and Benkő. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Szilvia Benkő, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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