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SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells

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SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells Mo et al. Respir Res (2021) 22:178 https://doi.org/10.1186/s12931-021-01757-1 RESEARCH Open Access SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells Yuqing Mo†, Ling Ye†, Hui Cai, Guiping Zhu, Jian Wang, Mengchan Zhu, Xixi Song, Chengyu Yang and Meiling Jin* Abstract Background: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic infammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SER- PINB10 afects the viability of Th2 cells. Methods: Th2 cytokines and serum levels of house dust mite (HDM)-specifc IgE in bronchoalveolar lavage fuid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by fow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantifed by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results: Knockdown of SERPINB10 expression signifcantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specifc IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion: Our results suggest that SERPINB10 may contribute to allergic infammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells. Keywords: Asthma, SERPINB10, Th2 response, Apoptosis Background [1]. Te T2 cells and the cytokines that typify the T2 Asthma is a common chronic infammatory disease char- cell subset underlies the inappropriate immune responses acterized by airway infammation, airway hyperrespon- that characterize allergic asthma [2]. Te “signature” siveness, mucus hyperproduction, and airway remodeling cytokines of T2 cells, interleukin (IL)-4, IL-5 and IL-13, have a central role in infltration of eosinophils and increased secretion of mucus [3, 4]. *Correspondence: [email protected] †Yuqing Mo and Ling Ye contributed equally to this work Serine protease inhibitors (SERPINS) are a superfam- Department of Pulmonary and Critical Care Medicine, Zhongshan ily of homologous proteins that have important roles Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, in infammation, immune-system function, apoptosis Shanghai 200032, China © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mo et al. Respir Res (2021) 22:178 Page 2 of 12 regulation [5, 6], and metastasis of cancer cells [7]. Table 1 Subject characteristics Human SERPINS are divided into nine groups (A–I) Asthma (n 16) = called “clades” according to their sequence similarity. Expression of several members in clade B, such as SER- Age, year 35 (18,66) PINB2, SERPINB3 and SERPINB4, is upregulated in Sex, M:F 6:10 Body mass index 23.8 3.6 allergic diseases, and they modulate T1/T2 responses ± FEV , % predict 90.6 13.6 [8–10]. Mice with SERPINB2 defciency have a defective 1 ± response from T2 cytokines after nematode infection FENO, ppb 40.5 (16.25, 88.25) [8]. SERPINB3 and SERPINB4 in patients sufering from Total IgE, IU/ml 254.0 (231.3, 340.5) Values were presented as mean (range) or mean SD or median with allergic disease control the viability of T2 cells by exert- ± interquartile range. FEV1, forced expiratory volume in the frst second; FENO, ing anti-apoptotic efects [11]. fraction of exhaled nitric oxide SERPINB10 is another member of clade B. Previously, we reported that SERPINB10 expression was increased in the bronchial epithelial cells of patients with asthma and instillation of HDM extract (10 μg; Greer Laboratories, was associated with airway eosinophilic infammation. Lenoir, NC, USA) in 40 μL of phosphate-bufered saline Knockdown of SERPINB10 expression can reduce airway (PBS) on days 0, 1, and 2. From day-8 to day-12, mice hyperresponsiveness and airway eosinophilic infamma- were challenged daily by intranasal administration of tion in a murine model of asthma [12]. Te role of SER- HDM (10 μg in 40 μL of PBS). Control mice were given, PINB10 in the T2 response of allergic asthma is not via the intranasal route, 40 μL of PBS during sensitization known. Schleef and colleagues reported that SERPINB10 and challenge phases. Two weeks before the frst sensi- can inhibit tumor necrosis factor α (TNF-α)-induced cell tization, mice were administered 30 µL AAV containing death [13]. Terefore, we hypothesized that SERPINB10 SERPINB10 shRNA or scrambled shRNA. Mice were may participate in the T2 response of allergic asthma by sacrifced for evaluation on day-14. Tere were fve to six afecting the apoptosis of T2 cells. mice per group for each independent experiment. We investigated the efect of knockdown of SERPINB10 expression on the T2 response and apoptosis of T cells RT‑qPCR and Western blotting in a house dust mite (HDM)-induced model of asthma. RT-qPCR and Western blotting were performed as We measured expression of SERPINB10 in polarized T1 our previous study [12] and the protocol is given in the and T2 cells derived from patients with asthma. We Additional fle 2: Materials and Methods. Te primer assessed the efect of SERPINB10 on the apoptosis of T sequences of all genes for PCR are listed in Additional cells in vitro. fle 1: Table S1. Methods Analyses of bronchoalveolar lavage fuid (BALF) Mouse model BALF was collected according to a method described Female C57BL/6 J mice (6–8 weeks) were purchased previously [14]. Briefy, the trachea was cannulated from JSJ Laboratory (Shanghai, China) and bred under through a 22-inch intravenous catheter and the lungs specifc pathogen-free conditions at the animal center were lavaged with a total volume of 1 mL PBS for three of Zhongshan Hospital, Fudan University (Shanghai, successive aspirations to obtain BALF. Te BALF was China). All experimental protocols were approved by the centrifuged at 500 g for 8 min at 4 ℃. Te cell-free Animal Care and Use Committee of Zhongshan Hospi- × supernatant was collected for cytokine analyses using tal. Mice were anesthetized with isofurane and adminis- ELISA kits. Cell pellets were resuspended in PBS and the tered, via the intratracheal route, adeno-associated virus total cell number was counted using CellDrop® (DeNo- (AAV) (30 µL; 6.32 ­1012 viral particles/mL; Vigene Bio- × vix, Wilmington, DE, USA). Cells were analyzed by fow sciences, Shandong, China) containing SERPINB10 short cytometry using PE-conjugated anti-SiglecF (eBiosci- hairpin (sh)RNA or scrambled shRNA. Te sequence ence, San Diego, CA, USA), FITC-conjugated anti-CD3 of SERPINB10 shRNA was GCA GAA CCA CAA TCT (BD Biosciences, San Jose, CA, USA), APC-conjugated GTT AAC TTC AAG AGA GTT AAC AGA TTG TGG TTC anti-CD11c (Multiscience, Zhejiang, China), FITC-con- TGC TTT TTT. After 2 weeks, the mice were sacri- jugated anti-CD19 (BioLegend, San Diego, CA, USA), fced to evaluate the knockdown efciency of Serpinb10 Percp-cy5.5-conjugated anti-Ly6G (BioLegend) and AAV. Another batch of mice was used to establish an PE-cy7-conjugated anti-MHC II (BioLegend). Te fow HDM asthma model. Mice were randomly divided into cytometry gating strategy was according to a method three groups: control group, asthma group and knock- described previously [15]. down asthma group. Mice were sensitized by intranasal Mo et al. Respir Res (2021) 22:178 Page 3 of 12 Flow cytometry of lung tissues predicted following inhalation of 200 μg of salbutamol). We wished to calculate the number of T cells in lungs. None of the patients had ever received inhaled or oral Lung tissues were immersed in Hank’s medium contain- corticosteroid or leukotriene antagonist. Demographic ing collagenase IV (1 mg/mL) and DNase I (20 μg/mL). information (Table 1) and blood samples from 16 patients Lung tissues were ground using a gentleMACS® Disso- were collected for study. Written informed consent was ciator (Miltenyi Biotec, Bergisch Gladbach, Germany) obtained from all patients. Tis study was approved and then incubated with shaking at 100 rpm for 30 min by the ethics committee of Zhongshan hospital, Fudan at 37 ℃.
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