Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Nov 2:9:733308.
doi: 10.3389/fcell.2021.733308. eCollection 2021.

Butyric Acid Protects Against Renal Ischemia-Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Zhen Chen  1 , Miaomiao Wang  1 , Shikun Yang  2 , Jian Shi  1 , Tianhao Ji  2 , Wei Ding  1   3 , Lianghua Jiang  4 , Zhiwen Fan  5 , Jing Chen  1 , Yunjie Lu  1
Affiliations

Butyric Acid Protects Against Renal Ischemia-Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Zhen Chen et al. Front Cell Dev Biol. .

Erratum in

Abstract

Immune regulation plays a vital role in ischemia-reperfusion injury (IRI). Butyric acid (BA) has immunomodulatory effects in many diseases, but its immunomodulatory effects during renal IRI are still unclear. Our research shows that BA protected against IRI and significantly improved renal IRI in vivo. In vitro studies showed that BA inhibits Th17 cell differentiation and induces Treg cell differentiation. Mechanism studies have shown that heme oxygenase 1 (HO-1)/STAT3 signaling pathway was involved in the inhibitory effect of BA on Th17 cell differentiation. HO-1 inhibitors can significantly rescue the BA-mediated inhibition of Th17 cell differentiation. We confirmed that BA promotes the differentiation of Th17 cells into Treg cells by regulating the pathway and reduces renal IRI.

Keywords: HO-1; STAT3; Th17; Treg; butyric acid; renal ischemia–reperfusion injury.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
BA treatment ameliorated renal IRI. (A) Mice were orally administered BA and DMSO 3 days before surgery. (B,C) BUN and Cr of mice on the first day after surgery were tested. (D) HE staining of kidneys in the BA treatment group showed alleviate renal tubular damage, renal tubular epithelial cells atrophy, degeneration, necrosis, and extensive lesion range than control group. (E) BA treatment significantly reduced the tubular injury Paller score in IRI mice. Sample size = 3 in each group. Data were presented as mean ± standard deviation. N.S. P > 0.05, *P < 0.05, **P < 0.01.
FIGURE 2
FIGURE 2
BA regulates Foxp3 expression, cell expansion, and the function of CD4+ iTregs and inhibited IL-17A+ Treg cell differentiation in vitro. (A–C) Renal cortex homogenate was collected to assay the anti-inflammatory effects of BA. The inflammatory cytokines IL-17A, IL-6 were significantly decreased after the treatment of BA in kidney IRI, while IL-10 was significantly increased. CD4+ cells (CD4+CD62LHighCD44Low) isolated from C57/B6J mouse spleens were cultured under Treg polarizing conditions with BA or placebo. The expression of Foxp3 was significantly increased in the cells treated by BA within 8 days after induction. Compared with the control group, the absolute number of CD4+ iTregs in BA group was slightly increased on day 8 while the difference was not significant on day 8. The suppressive ability of BA-CD4+ iTregs was estimated by CFSE coculture assays. Although there was no difference in suppressive ability at 1:1 (Treg:CD4+ effector T cells), BA-CD4+ iTregs showed stronger inhibition at 1:8. We used bisulfite sequence analysis to detect the methylation status of CD4+ iTregs induced by BA. And compared with the control group, there were fewer methylated CpG sites in BA-CD4+ iTregs. Sample size = 3 in each group. Data were presented as mean ± standard deviation. N.S. P > 0.05, *P < 0.05, **P < 0.01.
FIGURE 3
FIGURE 3
BA regulates Treg/Th17 balance by targeting SOCS3 but not SOCS1 in renal IRI. (A) The frequency of Th17 cells in the BA treatment group was significantly reduced. (B,C) The expression of RORγt and SOCS3, but not SOCS1 was decreased after BA treatment. Sample size = 3 in each group. Data were presented as mean ± standard deviation. N.S. P > 0.05, *P < 0.05, **P < 0.01.
FIGURE 4
FIGURE 4
BA protects against renal IRI via p-STAT3/SOCS3 signaling. (A,B) BA treatments attenuated the expression of p-STAT3 but not p-JAK2. (C,D) After BRL52537 treatment, the expression of p-STAT3 but not p-JAK2 was increased. (E–G) BRL52537 significantly attenuated the anti-inflammatory effects of BA on renal IRI. (H) HE staining indicated that BRL52537 significantly attenuated the protective effects of BA on renal IRI. Sample size = 3 in each group. Data were presented as mean ± standard deviation. N.S. P > 0.05, *P < 0.05, **P < 0.01.
FIGURE 5
FIGURE 5
HO-1/p-STAT3 signaling pathway was implicated in Treg/Th17 balance mediated by BA. (A,B) SnPP (the inhibitor of HO-1), significantly reduced the up-regulation of BA-related p-STAT3 expression. (C) In CD4+ T cells under Treg/TH17 polarizing conditions. BA/Snpp co-treatment reversed the immunological balance of Treg/Th17 cells by BA only. (D) HE staining show that SnPP treatment significantly, but not wholly, reversed the regulating effect of BA. Sample size = 3 in each group. Data were presented as mean ± standard deviation. N.S. P > 0.05, *P < 0.05, **P < 0.01.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Arpaia N., Campbell C., Fan X., Dikiy S., van der Veeken J., deRoos P., et al. (2013). Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504 451–455. 10.1038/nature12726 - DOI - PMC - PubMed
    1. Barbi J., Pardoll D., Pan F. (2014). Treg functional stability and its responsiveness to the microenvironment. Immunol. Rev. 259 115–139. 10.1111/imr.12172 - DOI - PMC - PubMed
    1. Brunstein C. G., Miller J. S., McKenna D. H., Hippen K. L., DeFor T. E., Sumstad D., et al. (2016). Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood 127 1044–1051. 10.1182/blood-2015-06-653667 - DOI - PMC - PubMed
    1. Cao T., Zhang X., Chen D., Zhang P., Li Q., Muhammad A. (2018). The epigenetic modification during the induction of Foxp3 with sodium butyrate. Immunopharmacol. Immunotoxicol. 40 309–318. 10.1080/08923973.2018.1480631 - DOI - PubMed
    1. Chen Z., Barbi J., Bu S., Yang H. Y., Li Z., Gao Y., et al. (2013). The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39 272–285. 10.1016/j.immuni.2013.08.006 - DOI - PMC - PubMed