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Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly.

ABSTRACT: Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.

SUBMITTER: De Maeyer RPH

PROVIDER: S-EPMC7983074 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dioscin has been shown to affect the regulation of metabolic diseases, including diabetes; however, the mechanism of action is still unclear. Under high glucose (HG) conditions, the expression of scavenger receptors and the uptake of oxidized low‑density lipoprotein (oxLDL) are upregulated in dendritic cells (DCs), which are critical steps in atherogenesis and inflammation. In this study, the focus was on the impact of dioscin on the function of DCs. Immature DCs were cultured with: 5.5 mM glucose medium (control group); 30 mM glucose medium (HG group); HG + 10 mM dioscin; HG + 20 mM dioscin; HG + 30 mM dioscin; and HG + 40 mM dioscin. For subsequent experiments, 30 mM dioscin was used as the experimental concentration. Dichlorodihydrofluorescein fluorescence was used to measure the intracellular production of reactive oxygen species (ROS) in DCs. The expression levels of the scavenger receptors, including class A scavenger receptors (SR‑A), CD36 and lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1) were determined via quantitative PCR. The protein expression of p38 mitogen‑activated protein kinase (MAPK) was determined by western blotting. Furthermore, ELISA was used to detect the levels of interleukin (IL)‑6, IL‑10 and IL‑12. Finally, DCs were incubated with diOlistic (Dil)‑labeled oxLDL, and flow cytometry analysis was used to investigate the Dil‑oxLDL‑incorporated fraction. The incubation of DCs with dioscin inhibited the induction of ROS production, in a dose‑dependent manner, under HG conditions. The upregulation of SR‑A, CD36 and LOX‑1 genes was partially abolished by dioscin, which also partially reversed p38 MAPK protein upregulation. Furthermore, increased secretion of IL‑6 and IL‑12, and decreased secretion of IL‑10 in DCs, induced by HG, was also reversed by dioscin. To conclude, dioscin could attenuate the production of ROS, inflammatory cytokine secretion and oxLDL uptake by DCs in HG conditions by preventing the expression of scavenger receptors and p38 MAPK, thus playing a positive role in preventing atherogenesis.

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Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly.

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