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. 2024 May 2:15:1367053.
doi: 10.3389/fimmu.2024.1367053. eCollection 2024.

Intestinal microflora promotes Th2-mediated immunity through NLRP3 in damp and heat environments

Yi Luo #  1   2 , Xinhua Huang #  2 , Haiying Hu #  3 , Yao Wang  2 , Xiangrong Feng  2 , Song Chen  4 , Huanhuan Luo  1   2
Affiliations

Intestinal microflora promotes Th2-mediated immunity through NLRP3 in damp and heat environments

Yi Luo et al. Front Immunol. .

Abstract

Background: With the worsening of the greenhouse effect, the correlation between the damp-heat environment (DH) and the incidence of various diseases has gained increasing attention. Previous studies have demonstrated that DH can lead to intestinal disorders, enteritis, and an up-regulation of NOD-like receptor protein 3 (NLRP3). However, the mechanism of NLRP3 in this process remains unclear.

Methods: We established a DH animal model to observe the impact of a high temperature and humidity environment on the mice. We sequenced the 16S rRNA of mouse feces, and the RNA transcriptome of intestinal tissue, as well as the levels of cytokines including interferon (IFN)-γ and interleukin (IL)-4 in serum.

Results: Our results indicate that the intestinal macrophage infiltration and the expression of inflammatory genes were increased in mice challenged with DH for 14 days, while the M2 macrophages were decreased in Nlrp3 -/- mice. The alpha diversity of intestinal bacteria in Nlrp3 -/- mice was significantly higher than that in control mice, including an up-regulation of the Firmicutes/Bacteroidetes ratio. Transcriptomic analysis revealed 307 differentially expressed genes were decreased in Nlrp3 -/- mice compared with control mice, which was related to humoral immune response, complement activation, phagocytic recognition, malaria and inflammatory bowel disease. The ratio of IFN-γ/IL-4 was decreased in control mice but increased in Nlrp3 -/- mice.

Conclusions: Our study found that the inflammation induced by DH promotes Th2-mediated immunity via NLRP3, which is closely related to the disruption of intestinal flora.

Keywords: NLRP3; Th2-mediated immunity; damp-heat environment; intestinal microflora; transcriptome.

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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
The characterization of mice and ileum macrophages in damp and heat environments (DH). (A) Fur changes in mice on day 14. (B) Weight changes in mice from each group. (C-E) Immunohistochemical staining of macrophages in intestinal tissues. C57 mice model of humid and hot environment (C-DH). C57 mice in the normal control environment (C-NC). Nlrp3-/- mice model of humid and hot environment (K-DH). Nlrp3-/- mice in the normal control environment (K-NC). F4/80 marking total macrophage count. CD11c marking M1 macrophages. CD206 marking M2 macrophages. *P<0.05. **P<0.01. ***P<0.001.
Figure 2
Figure 2
Differential gut microbiota induced by DH. (A) Principal Component Analysis of mice. (B, C) Shannon and Simpson index of intestinal microbiota in mice. (D-F) Comparison of phylum, class, and genus levels of intestinal microbiota in mice. (G-O) Comparison of species abundance of Firmicutes and other bacteria in mouse gut. C57 mice model of humid and hot environment (C-DH). C57 mice in the normal control environment (C-NC). Nlrp3-/- mice model of humid and hot environment (K-DH). Nlrp3-/- mice in the normal control environment (K-NC). *P<0.05. **P<0.01. ***P<0.001.
Figure 3
Figure 3
Functional analysis of differential intestinal bacteria. (A-C) Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in mice intestinal microbiota. C57 mice model of humid and hot environment (C-DH). C57 mice in the normal control environment (C-NC). Nlrp3-/- mice model of humid and hot environment (K-DH). Nlrp3-/- mice in the normal control environment (K-NC).
Figure 4
Figure 4
Differential genes and functional analysis in mice transcriptome. (A-D) Volcano plot representing differentially expressed genes in mice gut. (E-H) Enrichment of GO functions in differentially expressed genes in mice gut. C57 mice model of humid and hot environment (C-DH). C57 mice in the normal control environment (C-NC). Nlrp3-/- mice model of humid and hot environment (K-DH). Nlrp3-/- mice in the normal control environment (K-NC).
Figure 5
Figure 5
Differential cytokines and analysis function in mice serum. (A-D) Principal Component Analysis of serum cytokines in mice. Heatmap clustering of significantly different cytokines in mice serum. (E, F) Comparison of IFN-/IL-4 and IL-4/IL-10 ratios in mice serum. (G-J) Enrichment of KEGG pathways in differentially expressed cytokines in mouse serum. C57 mice model of humid and hot environment (C-DH). C57 mice in the normal control environment (C-NC). Nlrp3-/- mice model of humid and hot environment (K-DH). Nlrp3-/- mice in the normal control environment (K-NC). *P < 0.05.
Figure 6
Figure 6
Possible mechanisms of NLRP3 and gut microbiota regulation of Th1/Th2 immunity in DH.
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