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. 2024 Jun 18;25(12):6706.
doi: 10.3390/ijms25126706.

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation

Dongwan Zhang  1 , Wang Jiang  1 , Yan Yu  1 , Jingjing Huang  1 , Zhihui Jia  1 , Yuli Cheng  1 , Xinping Zhu  1
Affiliations

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation

Dongwan Zhang et al. Int J Mol Sci. .

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.

Keywords: CD4+ T cells; T cell differentiation; Trichinella spiralis paramyosin; collagen-induced arthritis; hygiene hypothesis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mitigable effects of rTs-Pmy on collagen-induced arthritis (CIA) in DBA/1 mice. (A) The regimen of study including the induction of CIA and treatment with rTs-Pmy. Collagen-induced arthritis was induced in male DBA/1 mice. Yellow: prior rTs-Pmy injection group, green: post rTs-Pmy injection group, blue: CII immunization/boost, red: sacrifice. (B) Body weight; (C) arthritic scores (0–16); (D) arthritic Incidence (%); (E) hematoxylin and eosin staining of the representative inflamed joints in the hind paw of mice from different groups at day 38 after the first CII immunization, with the histological score shown on the right. Black arrows indicate synovial hyperplasia, cartilage destruction, inflammatory cell infiltration, and pannus formation. Scale bar: 200 µm. n = 5/group, data are shown with mean ± SEM (** p < 0.01 and **** p < 0.0001 vs. CIA group by one-way ANOVA test, ns indicates no significant difference).
Figure 2
Figure 2
Administration of rTs-Pmy alleviates systemic CD4+ T cell immune imbalance in CIA mice. (A) The concentration of serum cytokines in of mice different groups; (B) the concentration of cytokines in the supernatant of mouse splenocytes stimulated with Cell Stimulation Cocktail for 16 h; (C) flow cytometry gating strategy for CD3+CD4+ T cells. Single cells were gated from lymphocytes, and CD3+CD4+ T cells were gated from single cells; (D–G) the proportion of Th1 (D), Th2 (E), Th17 (F) cells and Tregs (G) in CD3+CD4+ T cells. n = 5 mice/group, data are shown with mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001 vs. CIA group by one-way ANOVA test, ns indicates no significant difference).
Figure 3
Figure 3
Administration of rTs-Pmy ameliorated the immune imbalance of CD4+ T cells in CIA mice paw joints. (A) The concentration of cytokines in paws of mice in each group; (B) number of CD4+ T cells in paws, scale bar: 50 μm; (C) the expression level of transcription factors in CD4+ T cells. n = 5/group, data are shown with mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001 vs. CIA group by one-way ANOVA test, ns indicates no significant difference).
Figure 4
Figure 4
rTs-Pmy inhibited the differentiation of CD4+ T cells in the direction of Th1 and Th17 in vitro through the presentation of BMDCs. (A) BMDC and Th1/Th17 co-culture experiment procedure; (B) gating strategy. Single cells were gated from lymphocytes, and CD3+CD4+ T cells were gated from single cells; (C) the proportion of CD4+IFN-γ+ Th1 cells in Th1 induction group; (D) the proportion of CD4+IL-4+ Th2 cells in Th1 induction group; (E) the proportion of CD4+IL-17A+ Th17 cells in Th17 induction group; (F) the proportion of CD25+Foxp3+ Th1 cells in Th17 induction group. n = 3/group, data are shown with mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001 vs. Th1/17 induction group by one-way ANOVA test, ns indicates no significant difference).
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