Open Access

Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model

  • Authors:
    • Xian Zhang
    • Qianqian Dai
    • Jiajia Shan
    • Shiyun Zhang
    • Bin Zhang
    • Siyang Liu
    • Yixue Zhang
    • Ying Wang
    • Xiaojie Li
    • Xuguang Jin
    • Dongmei Liang
    • Jingjing Ding
    • Yong Wang
    • Yanting Wen
  • View Affiliations

  • Published online on: March 30, 2023     https://doi.org/10.3892/etm.2023.11923
  • Article Number: 225
  • Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)‑related non‑caseating granulomas. Phosphoinositide‑3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL‑101 (PI3Kδ inhibitor) or AS‑605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence‑activated cell sorting analysis and reverse transcription‑quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA‑induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25‑ T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL‑101/AS‑605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL‑101 was more effective in immune modulation compared with AS‑605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs‑mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune‑therapeutic principle for sarcoidosis in the future.
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May-2023
Volume 25 Issue 5

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Spandidos Publications style
Zhang X, Dai Q, Shan J, Zhang S, Zhang B, Liu S, Zhang Y, Wang Y, Li X, Jin X, Jin X, et al: Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model. Exp Ther Med 25: 225, 2023
APA
Zhang, X., Dai, Q., Shan, J., Zhang, S., Zhang, B., Liu, S. ... Wen, Y. (2023). Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model. Experimental and Therapeutic Medicine, 25, 225. https://doi.org/10.3892/etm.2023.11923
MLA
Zhang, X., Dai, Q., Shan, J., Zhang, S., Zhang, B., Liu, S., Zhang, Y., Wang, Y., Li, X., Jin, X., Liang, D., Ding, J., Wang, Y., Wen, Y."Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model". Experimental and Therapeutic Medicine 25.5 (2023): 225.
Chicago
Zhang, X., Dai, Q., Shan, J., Zhang, S., Zhang, B., Liu, S., Zhang, Y., Wang, Y., Li, X., Jin, X., Liang, D., Ding, J., Wang, Y., Wen, Y."Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model". Experimental and Therapeutic Medicine 25, no. 5 (2023): 225. https://doi.org/10.3892/etm.2023.11923