Intracellular serpin A1 regulates inflammatory cytokines expression via toll-like receptor signaling pathway in endometrial stromal cells

Kazuya Kusama, Ayaka Satoyoshi, Mana Azumi, Mikihiro Yoshie, Takeshi Kajihara, Kazuhiro Tamura
In: Proceedings for Annual Meeting of The Japanese Pharmacological Society · 2022 · vol. 96(0) , pp. 4–B · doi:10.1254/jpssuppl.96.0_4-b-p-319 · W4313198949
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Silencing SERPINA1 in endometrial stromal cells upregulates TLR3/4 signaling and inflammatory cytokines, suggesting that reduced SERPINA1 exacerbates inflammation in endometriotic lesions.

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This study investigated the role of serpin A1 (SERPINA1) in regulating inflammatory cytokine expression within endometrial stromal cells. Researchers utilized RNA-seq analysis and gene silencing techniques to demonstrate that reduced SERPINA1 levels lead to the upregulation of toll-like receptors 3 and 4, along with their downstream factor MYD88. The findings indicate that this TLR3/4 signaling pathway mediates increased inflammation, a mechanism confirmed by immunohistochemical localization of these proteins in endometriotic lesions. This paper is centrally about endometriosis — specifically focusing on the molecular mechanisms involving SERPINA1 deficiency and Toll-like receptor signaling in endometrial stromal cells.

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Abstract

Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. We have previously found that serpin A1 (SERPINA1) was decreased in the endometriosis-like lesion of the mouse model, which makes us hypothesize that a decrease in SERPINA1 may exacerbate inflammation in the lesion. However, the molecular mechanisms by which SERPINA1 affects the expression of inflammatory cytokines and the development of endometriosis remains unclear. To investigate the role of SERPINA1 in endometrial stromal cells (ESCs), RNA-seq analysis was performed using RNA extracted from ESCs knocking down SERPINA1. The analysis has identified several toll-like receptor (TLR)-related factors as the upregulated genes. Silencing SERPINA1 expression increased the expression of TLR3, TLR4, their downstream factor MYD88, and inflammatory cytokines in cultured ESCs. Treatment with TLR3 or TLR4 agonists enhanced the expression of inflammatory cytokines, whereas inhibitors of TLR3 or TLR4 decreased the expression of these cytokines in SERPINA1-silenced ESCs. Immunohistochemical analysis showed that TLR3, TLR4, and MYD88 were localized in the endometriotic lesion. Thus, our data indicate that the decrease in SERPINA1 induces the expression of inflammatory cytokines in ESCs, accompanying with TLR3/4 signaling. The regulation of intracellular SERPINA1 could be a potential strategy to inhibit inflammatory responses in endometriotic lesions.
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第96回日本薬理学会年会 セッションID: 96_4-B-P-319 会議情報 主催: 公益社団法人日本薬理学会 会議名: 第96回日本薬理学会年会 回次: 96 開催地: 横浜 開催日: 2022/11/30 - 2022/12/03 一般演題（ポスター） 子宮内膜間質細胞のSerpin A1によるToll様受容体シグナル経路を介した炎症性サイトカイン発現の調節 詳細 抄録 Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. We have previously found that serpin A1 (SERPINA1) was decreased in the endometriosis-like lesion of the mouse model, which makes us hypothesize that a decrease in SERPINA1 may exacerbate inflammation in the lesion. However, the molecular mechanisms by which SERPINA1 affects the expression of inflammatory cytokines and the development of endometriosis remains unclear. To investigate the role of SERPINA1 in endometrial stromal cells (ESCs), RNA-seq analysis was performed using RNA extracted from ESCs knocking down SERPINA1. The analysis has identified several toll-like receptor (TLR)-related factors as the upregulated genes. Silencing SERPINA1 expression increased the expression of TLR3, TLR4, their downstream factor MYD88, and inflammatory cytokines in cultured ESCs. Treatment with TLR3 or TLR4 agonists enhanced the expression of inflammatory cytokines, whereas inhibitors of TLR3 or TLR4 decreased the expression of these cytokines in SERPINA1-silenced ESCs. Immunohistochemical analysis showed that TLR3, TLR4, and MYD88 were localized in the endometriotic lesion. Thus, our data indicate that the decrease in SERPINA1 induces the expression of inflammatory cytokines in ESCs, accompanying with TLR3/4 signaling. The regulation of intracellular SERPINA1 could be a potential strategy to inhibit inflammatory responses in endometriotic lesions. © 2022 本論文著者

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