Age-mediated gut microbiota dysbiosis promotes the loss ofdendritic cells tolerance

Abstract

The old age-related loss of immune tolerance inflicts a person with a wide range ofautoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels of theimmune system that maintain immune tolerance through cytokines and regulatoryT-cells generation. Aging disturbs the microbial composition of the gut, causing im-mune system dysregulation. However, the vis-à-vis role of gut dysbiosis on DCs tol-erance remains highly elusive. Consequently, we studied the influence of aging ongut dysbiosis and its impact on the loss of DC tolerance. We show that DCs gener-ated from either the aged (DCOld) or gut-dysbiotic young (DCDysbiotic) but not young(DC Young) mice exhibited loss of tolerance, as evidenced by their failure to optimallyinduce the generation of Tregs and control the overactivation of CD4+ T cells. Themechanism deciphered for the loss of DCOld and DC Dysbiotic tolerance was chieflythrough the overactivation of NF-κB, impaired frequency of Tregs, upregulation inthe level of pro-inflammatory molecules (IL-6, IL-1β, TNF-α, IL-12, IFN-γ), and declinein the anti-inflammatory moieties (IL-10, TGF-β, IL-4, IDO, arginase, NO, IRF-4, IRF-8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency of theLactobacillus genus was noticed in the gut. Replenishing the gut of old mice with theLactobacillus plantarum reinvigorated the tolerogenic function of DCs through the re-wiring of inflammatory and metabolic pathways. Thus, for the first time, we demon-strate the impact of age- related gut dysbiosis on the loss of DC tolerance. This findingmay open avenues for therapeutic intervention for treating age-associated disorderswith the Lactobacillus plantarum.