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The p,p'-DDE disturbs the M1 function without affecting the M2 phenotype nor unstimulated bone marrow-derived
Vanessa Cortés-Montoya1, Christian D Ortiz-Robles1, Omar B Rivera-Maya1
1Center for Research and Advanced Studies of the National Polytechnic Institute, Department of Toxicology, Ciudad de México, Mexico.
Abstract:
DDT, a persistent organic pollutant, remains affecting human health worldwide. DDT and its most persistent metabolite (p,p'-DDE) negatively affect the immune response regulation and mechanisms involved in protecting against pathogens Such metabolite decreases the capability to limit intracellular growth of Mycobacterium microti and yeast. However, the effect on unstimulated (M0) and anti-inflammatory macrophages (M2) has been evaluated scanty. Herein, we evaluated the impact of p,p'-DDE at environmentally relevant concentrations (0.125, 1.25, 2.5, and 5 µg/mL) on bone marrow-derived macrophages stimulated with IFNγ+LPS to M1 or with IL-4 +IL-13 to M2. Thus we study whether the p,p'-DDE induces M0 to a specific phenotype or modulates activation of the macrophage phenotypes and explains, at least partly, the reported effects of p,p'-DDE on the M1 function. The p,p'-DDE did not affect the cell viability of M0 or the macrophage phenotypes. In M1, the p,p'-DDE decreased NO•- production and IL-1β secretion, but increasing cellular ROS and mitochondrial O2•-, but did not alter iNOS, TNF-α, MHCII, and CD86 protein expression nor affect M2 markers arginase activity, TGF-β1, and CD206; p,p'-DDE, did not affect marker expression in M0 or M2, supporting that its effects on M1 parameters are not dependent on M0 nor M2 modulation. The decreasing of NO•- production by the p,p'-DDE without altering iNOS levels, Arginase activity, or TNF-α, but increasing cellular ROS and mitochondrial O2 suggests that p,p'-DDE interferes with the iNOS function but not with its transcription. The p,p'-DDE decreasing of IL-1β secretion, without any effect on TNF-α, suggest that an alteration of specific targets involved in IL-1β secretion may be affected and related to ROS induction. The p,p'-DDE effect on iNOS function and the IL-1β secretion process, as the NLRP3 activation, deserves further study.
Insights
The persistent organic pollutant p,p'-DDE impairs macrophage immune function by reducing nitric oxide and IL-1β secretion, while increasing oxidative stress, without affecting cell viability or M2 markers.
Area of Science:
- Immunology
- Environmental Toxicology
- Cell Biology
Background:
- DDT (dichlorodiphenyltrichloroethane) and its metabolite p,p '-DDE are persistent organic pollutants with known immunomodulatory effects.
- Previous studies indicate p,p '-DDE impairs host defense against pathogens by affecting immune regulation.
- The impact of p,p '-DDE on unstimulated (M0) and anti-inflammatory (M2) macrophages remains underexplored.
Purpose of the Study:
- To investigate the effects of environmentally relevant concentrations of p,p '-DDE on M0, M1 (pro-inflammatory), and M2 macrophages.
- To determine if p,p '-DDE induces a specific phenotype in M0 macrophages or modulates M1/M2 activation.
- To elucidate the mechanisms underlying p,p '-DDE's reported effects on M1 macrophage function.
Main Methods:
- Bone marrow-derived macrophages were differentiated into M0, M1 (IFNγ+LPS stimulated), or M2 (IL-4+IL-13 stimulated) phenotypes.
- Macrophages were treated with p,p '-DDE at concentrations ranging from 0.125 to 5 µg/mL.
- Assessed cell viability, nitric oxide (NO•-) production, reactive oxygen species (ROS), mitochondrial superoxide (O2•-), and protein/activity levels of key inflammatory markers (iNOS, TNF-α, IL-1β, Arginase, TGF-β1, CD206, MHCII, CD86).
Main Results:
- p,p '-DDE did not affect the viability or phenotype markers of M0, M1, or M2 macrophages.
- In M1 macrophages, p,p '-DDE decreased NO•- production and IL-1β secretion.
- p,p '-DDE increased cellular ROS and mitochondrial O2•- in M1 macrophages but did not alter iNOS, TNF-α, MHCII, or CD86 expression. M2 markers remained unaffected.
Conclusions:
- p,p '-DDE impairs M1 macrophage function by interfering with nitric oxide production and IL-1β secretion, potentially through mechanisms involving oxidative stress.
- The observed effects on M1 macrophages are not due to altered M0 or M2 phenotypes, suggesting direct modulation of M1-specific pathways.
- Further research is warranted to explore p,p '-DDE's impact on iNOS function, IL-1β secretion pathways, and NLRP3 inflammasome activation.
