PMID- 37161603
OWN - NLM
STAT- MEDLINE
DCOM- 20230615
LR  - 20230627
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 22
IP  - 6
DP  - 2023 Jun
TI  - Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells 
      tolerance.
PG  - e13838
LID - 10.1111/acel.13838 [doi]
LID - e13838
AB  - The old age-related loss of immune tolerance inflicts a person with a wide range 
      of autoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels 
      of the immune system that maintain immune tolerance through cytokines and 
      regulatory T-cells generation. Aging disturbs the microbial composition of the 
      gut, causing immune system dysregulation. However, the vis-a-vis role of gut 
      dysbiosis on DCs tolerance remains highly elusive. Consequently, we studied the 
      influence of aging on gut dysbiosis and its impact on the loss of DC tolerance. 
      We show that DCs generated from either the aged (DC(Old) ) or gut-dysbiotic young 
      (DC(Dysbiotic) ) but not young (DC(Young) ) mice exhibited loss of tolerance, as 
      evidenced by their failure to optimally induce the generation of Tregs and 
      control the overactivation of CD4(+) T cells. The mechanism deciphered for the 
      loss of DC(Old) and DC(Dysbiotic) tolerance was chiefly through the 
      overactivation of NF-kappaB, impaired frequency of Tregs, upregulation in the level 
      of pro-inflammatory molecules (IL-6, IL-1beta, TNF-alpha, IL-12, IFN-gamma), and decline in 
      the anti-inflammatory moieties (IL-10, TGF-beta, IL-4, IDO, arginase, NO, IRF-4, 
      IRF-8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency 
      of the Lactobacillus genus was noticed in the gut. Replenishing the gut of old 
      mice with the Lactobacillus plantarum reinvigorated the tolerogenic function of 
      DCs through the rewiring of inflammatory and metabolic pathways. Thus, for the 
      first time, we demonstrate the impact of age-related gut dysbiosis on the loss of 
      DC tolerance. This finding may open avenues for therapeutic intervention for 
      treating age-associated disorders with the Lactobacillus plantarum.
CI  - (c) 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & 
      Sons Ltd.
FAU - Bashir, Hilal
AU  - Bashir H
AUID- ORCID: 0000-0003-3605-1726
AD  - Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39A, 
      Chandigarh, 160036, India.
FAU - Singh, Sanpreet
AU  - Singh S
AD  - Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39A, 
      Chandigarh, 160036, India.
FAU - Singh, Raghwendra Pratap
AU  - Singh RP
AD  - Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39A, 
      Chandigarh, 160036, India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
FAU - Agrewala, Javed N
AU  - Agrewala JN
AUID- ORCID: 0000-0003-0227-1042
AD  - Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39A, 
      Chandigarh, 160036, India.
AD  - Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of 
      Technology, Ropar, Rupnagar, 140001, Punjab, India.
FAU - Kumar, Rashmi
AU  - Kumar R
AUID- ORCID: 0000-0003-3444-1018
AD  - Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39A, 
      Chandigarh, 160036, India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230509
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Cytokines)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Gastrointestinal Microbiome
MH  - Dysbiosis/metabolism
MH  - Cytokines/metabolism
MH  - Dendritic Cells/metabolism
MH  - Immune Tolerance
MH  - T-Lymphocytes, Regulatory/metabolism
PMC - PMC10265174
OTO - NOTNLM
OT  - aging
OT  - dendritic cells
OT  - dysbiosis
OT  - gut microbiota
OT  - immune response
OT  - tolerance
COIS- The authors declare that they have no conflict of interest.
EDAT- 2023/05/10 06:42
MHDA- 2023/06/15 06:41
PMCR- 2023/05/09
CRDT- 2023/05/10 04:03
PHST- 2023/03/14 00:00 [revised]
PHST- 2022/12/05 00:00 [received]
PHST- 2023/03/16 00:00 [accepted]
PHST- 2023/06/15 06:41 [medline]
PHST- 2023/05/10 06:42 [pubmed]
PHST- 2023/05/10 04:03 [entrez]
PHST- 2023/05/09 00:00 [pmc-release]
AID - ACEL13838 [pii]
AID - 10.1111/acel.13838 [doi]
PST - ppublish
SO  - Aging Cell. 2023 Jun;22(6):e13838. doi: 10.1111/acel.13838. Epub 2023 May 9.