Estradiol-induced inhibition of endoplasmic reticulum stress normalizes splenic CD4\u2009+\u2009T lymphocytes following hemorrhagic shock

Peng Wang,Shu-Guang Li,Chun-Yu Niu,Meng Yin,Yan-Xu Liu,Meng Zhao,Chen Wang,Ying Li,Li-Na Jiang,An-Ling Kang,Hong Zhang,Hui-Bo Du,Zi-Gang Zhao,Ze-Hua Fan,Ding-Ya Feng

doi:10.1038/s41598-021-87159-1

Peng Wang, Shu-Guang Li + Show 13 more

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https://doi.org/10.1038/s41598-021-87159-1

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Abstract

The aim is to investigate that 17β-estradiol (E2)/estrogen receptors (ERs) activation normalizes splenic CD4 + T lymphocytes proliferation and cytokine production through inhibition of endoplasmic reticulum stress (ERS) following hemorrhage. The results showed that hemorrhagic shock (hemorrhage through femoral artery, 38–42 mmHg for 90 min followed by resuscitation of 30 min and subsequent observation period of 180 min) decreased the CD4+ T lymphocytes proliferation and cytokine production after isolation and incubation with Concanavalin A (5 μg/mL) for 48 h, induced the splenic injury with evidences of missed contours of the white pulp, irregular cellular structure, and typical inflammatory cell infiltration, upregulated the expressions of ERS biomarkers 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 6 (ATF6). Either E2, ER-α agonist propyl pyrazole triol (PPT) or ERS inhibitor 4-Phenylbutyric acid administration normalized these parameters, while ER-β agonist diarylpropionitrile administration had no effect. In contrast, administrations of either ERs antagonist ICI 182,780 or G15 abolished the salutary effects of E2. Likewise, ERS inducer tunicamycin induced an adverse effect similarly to that of hemorrhagic shock in sham rats, and aggravated shock-induced effects, also abolished the beneficial effects of E2 and PPT, respectively. Together, the data suggest that E2 produces salutary effects on CD4+ T lymphocytes function, and these effects are mediated by ER-α and GPR30, but not ER-β, and associated with the attenuation of hemorrhagic shock-induced ERS.

Highlights

According to current data, death from hemorrhage represents a worldwide problem, with an estimated 1.9 million deaths and 1.5 million of which result from physical trauma in each y ear[1,2,3]
The animals were subjected to hemorrhagic shock or sham shock as described p reviously[21], and the spleens were collected for the C D4+ T lymphocytes isolation at three hours after end of fluid resuscitation or treatments
The current study demonstrated that either E2/estrogen receptors (ERs) activation or inhibition of Endoplasmic reticulum stress (ERS) alleviated hemorrhagic shockinduced decreases in proliferation and cytokine production of the CD4+ T lymphocytes, spleen injury and increase in expressions of GRP78 and activating transcription factor 6 (ATF6)

Summary

Introduction

Death from hemorrhage represents a worldwide problem, with an estimated 1.9 million deaths and 1.5 million of which result from physical trauma in each y ear[1,2,3]. Whether ERβ and GPR30 are involved in the beneficial effects of E2 on splenic CD4+ T lymphocytes following hemorrhagic shock remains unknown. Salutary effects of E2 have been reported in male rats following traumahemorrhage, it remains unclear whether the salutary effects of E2 on the function of splenic CD4+ T lymphocytes following hemorrhage shock are via attenuation of ERS. We hypothesized that E2 normalizes the function of splenic C D4+ T lymphocytes through inhibition of hemorrhagic shock-induced ERS, which is mediated by activation of ERs. To test it, the present study determined the splenic C D4+ T lymphocytes proliferation and cytokine production and splenic histopathology and ERS biomarkers expressions following trauma hemorrhage, and investigated the regulatory effects of E2, the agonist or antagonist of ERs, and the inhibitor or inducer of ERS on these hemorrhagic shock-induced adverse effects

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