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SCFAs promote intestinal double-negative T cells to regulate the inflammatory response mediated by NLRP3 inflammasome.
- Source :
-
Aging [Aging (Albany NY)] 2021 Sep 07; Vol. 13 (17), pp. 21470-21482. Date of Electronic Publication: 2021 Sep 07. - Publication Year :
- 2021
-
Abstract
- Short-chain fatty acids (SCFAs) are a product of intestinal bacteria metabolism. Our previous study has found that intestinal bacteria in patients with Alzheimer's disease (AD) can promote the activation of NLRP3 inflammasome and mediate neuroinflammation. In this study, we mainly explored the regulation of intestinal microenvironmental immunity by intestinal bacterial metabolite SCFAs and the mechanism of NLRP3 activation. First, wild-type (WT) and APP/PS1 mice were intervened with SCFAs. As a result, the proportion of double-negative T cells (CD3 <superscript>+</superscript> CD4 <superscript>-</superscript> CD8 <superscript>-</superscript> , DNTs) in the intestine was increased, SCFAs could promote the expression of intestinal NLRP3 and inflammatory factors (IL-18, IL-6 and TNF-α). Moreover, SCAFs could also promote the level of inflammatory factors in the cerebrospinal fluid (CSF) of mice and aggravate the cognitive impairment in AD mice. CD3 <superscript>+</superscript> T cells isolated from the spleen were pre-treated with SCFAs, followed by detection of the proportion of DNTs. Consequently, SCFAs could promote the formation of DNTs, activate OX40 signal and simultaneously up-regulate the protein expression of Bcl-2, Bcl-xl and Survivin. Knockdown of OX40 could inhibit SCFAs-induced differentiation of DNTs. The co-culture of DNTs and intestinal macrophages showed that DNTs could activate Fas/FasL-TNF-α signal and induce the activation of NLRP3 inflammasome. In AD mouse models, treatment with Fas and TNFR1 inhibitors could significantly inhibit SCFAs-induced NLRP3 activation and inflammatory factors, while attenuate the inflammatory response in the brain tissue of mice and improve the cognitive ability of mice, however, without significant effect on the level of DNTs. The present study showed that SCFAs can promote the formation of DNTs through OX40. DNTs could induce the activation of NLRP3 inflammasome and the release of inflammatory factors in macrophages through Fas/FasL-TNF-α signals, thereby increasing the level of inflammatory factors in the central nervous system. When Fas and TNFR1 were inhibited by suppressing the functions of DNTs and macrophages, the activation of NLRP3 was inhibited. DNTs are affected by SCFAs, which is a new mechanism of neuroinflammation in AD.
- Subjects :
- Alzheimer Disease metabolism
Alzheimer Disease pathology
Animals
Brain metabolism
Brain pathology
Cytokines metabolism
Disease Models, Animal
Fas Ligand Protein metabolism
Inflammation
Macrophages metabolism
Mice, Inbred C57BL
Mice, Transgenic
Receptors, OX40 metabolism
Tumor Necrosis Factor-alpha metabolism
fas Receptor metabolism
Mice
Fatty Acids, Volatile metabolism
Inflammasomes metabolism
Intestines immunology
Intestines metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Neuroinflammatory Diseases metabolism
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-4589
- Volume :
- 13
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Aging
- Publication Type :
- Academic Journal
- Accession number :
- 34491906
- Full Text :
- https://doi.org/10.18632/aging.203487