{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T05:07:31Z","timestamp":1768712851065,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T00:00:00Z","timestamp":1699747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004772","name":"Natural Science Foundation of Ningxia","doi-asserted-by":"publisher","award":["2023AAC03100"],"award-info":[{"award-number":["2023AAC03100"]}],"id":[{"id":"10.13039\/501100004772","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004772","name":"Natural Science Foundation of Ningxia","doi-asserted-by":"publisher","award":["2023AAC03201"],"award-info":[{"award-number":["2023AAC03201"]}],"id":[{"id":"10.13039\/501100004772","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tuberculosis (TB) is the leading cause of human death worldwide due to Mycobacterium tuberculosis (Mtb) infection. Mtb infection can cause macrophage pyroptosis. PERK, as a signaling pathway protein on the endoplasmic reticulum, plays an important role in infectious diseases. It is not clear whether PERK is involved in the regulation of pyroptosis of macrophages during Mtb infection. In this study, Bacillus Calmette\u2013Guerin (BCG) infection resulted in high expression of pro-caspase-1, caspase-1 p20, GSDMD-N, and p-PERK in the THP-1 macrophage, being downregulated with the pre-treatment of GSK2656157, a PERK inhibitor. In addition, GSK2656157 inhibited the secretion of IL-1\u03b2 and IL-18, cell content release, and cell membrane rupture, as well as the decline in cell viability induced by BCG infection. Similarly, GSK2656157 treatment downregulated the expressions of pro-caspase-1, caspase-1 p20, caspase-11, IL-1\u03b2 p17, IL-18 p22, GSDMD, GSDMD-N, and p-PERK, as well as reducing fibrous tissue hyperplasia, inflammatory infiltration, and the bacterial load in the lung tissue of C57BL\/6J mice infected with BCG. In conclusion, the inhibition of PERK alleviated pyroptosis induced by BCG infection, which has an effect of resisting infection.<\/jats:p>","DOI":"10.3390\/ijms242216239","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:10:43Z","timestamp":1699841443000},"page":"16239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette\u2013Guerin Infection"],"prefix":"10.3390","volume":"24","author":[{"given":"Boli","family":"Ma","sequence":"first","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyi","family":"Nie","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueyang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxin","family":"Hou","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-5460","authenticated-orcid":false,"given":"Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-8002","authenticated-orcid":false,"given":"Jinrui","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Ningxia University, Yinchuan 750021, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1016\/S0140-6736(19)30308-3","article-title":"Tuberculosis","volume":"393","author":"Furin","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/nrmicro.2017.128","article-title":"Pathogenesis of HIV-1 and Mycobacterium tuberculosis co-infection","volume":"16","author":"Bell","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1469-0691.2011.03556.x","article-title":"Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis","volume":"17","author":"Borrell","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1128\/microbiolspec.GPP3-0022-2018","article-title":"Immunology of Mycobacterium tuberculosis Infections","volume":"7","author":"Sia","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41392-021-00507-5","article-title":"Pyroptosis: Mechanisms and diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/imr.12909","article-title":"The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)","volume":"297","author":"Zheng","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41423-021-00670-3","article-title":"An update on the regulatory mechanisms of NLRP3 inflammasome activation","volume":"18","author":"Paik","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/s41590-021-00886-5","article-title":"NLRP3 inflammasome in cancer and metabolic diseases","volume":"22","author":"Sharma","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1038\/s41423-021-00740-6","article-title":"NLRP3 inflammasome activation and cell death","volume":"18","author":"Huang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature13683","article-title":"Inflammatory caspases are innate immune receptors for intracellular LPS","volume":"514","author":"Shi","year":"2014","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nature15514","article-title":"Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eabj3859","DOI":"10.1126\/sciimmunol.abj3859","article-title":"NLRP3 inflammasome activation triggers gasdermin D-independent inflammation","volume":"6","author":"Wang","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0966-842X(00)01945-4","article-title":"Dismantling the Cryptococcus coat","volume":"9","author":"Heitman","year":"2001","journal-title":"Trends Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1080\/19490976.2016.1182289","article-title":"Microbiota and caspase-1\/caspase-8 regulate IL-1\u03b2-mediated bone disease","volume":"7","author":"Phillips","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eaba4733","DOI":"10.1126\/sciadv.aba4733","article-title":"Mycobacterial EST12 activates a RACK1-NLRP3-gasdermin D pyroptosis-IL-1\u03b2 immune pathway","volume":"6","author":"Qu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.chom.2015.05.003","article-title":"Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1","volume":"17","author":"Wassermann","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1016\/j.bbamcr.2013.06.028","article-title":"ER stress-induced cell death mechanisms","volume":"1833","author":"Sano","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shacham, T., Patel, C., and Lederkremer, G.Z. (2021). PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?. Biomolecules, 11.","DOI":"10.3390\/biom11030354"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-immunol-032414-112116","article-title":"Endoplasmic reticulum stress in immunity","volume":"33","author":"Bettigole","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nature17631","article-title":"NOD1 and NOD2 signalling links ER stress with inflammation","volume":"532","author":"Byndloss","year":"2016","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41590-022-01145-x","article-title":"PERK is a critical metabolic hub for immunosuppressive function in macrophages","volume":"23","author":"Raines","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Di Conza, G., and Ho, P.C. (2020). ER Stress Responses: An Emerging Modulator for Innate Immunity. Cells, 9.","DOI":"10.3390\/cells9030695"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1080\/15548627.2019.1687214","article-title":"BAG2 ameliorates endoplasmic reticulum stress-induced cell apoptosis in Mycobacterium tuberculosis-infected macrophages through selective autophagy","volume":"16","author":"Liang","year":"2020","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1093\/femsre\/fuz006","article-title":"Mycobacterium tuberculosis infection of host cells in space and time","volume":"43","author":"Bussi","year":"2019","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.chom.2018.08.001","article-title":"Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination","volume":"24","author":"Cohen","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1080\/22221751.2020.1861913","article-title":"Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis","volume":"10","author":"Guo","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"633360","DOI":"10.3389\/fcimb.2021.633360","article-title":"Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics against Mycobacterial Infection","volume":"11","author":"Silwal","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Allen, I.C., Mcelvania-Tekippe, E., Wilson, J.E., Lich, J.D., Arthur, J.C., Sullivan, J.T., Braunstein, M., and Ting, J.P. (2013). Characterization of NLRP12 during the in vivo host immune response to Klebsiella pneumoniae and Mycobacterium tuberculosis. PLoS ONE, 8.","DOI":"10.1371\/annotation\/2190ebe1-452c-4966-9f74-9813378524d4"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12943-018-0900-3","article-title":"Role of the NLRP3 inflammasome in cancer","volume":"17","author":"Moossavi","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100887","DOI":"10.1016\/j.mam.2020.100887","article-title":"NLRP12 in innate immunity and inflammation","volume":"76","author":"Tuladhar","year":"2020","journal-title":"Mol. Asp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1146\/annurev-immunol-073119-095439","article-title":"Caspases in Cell Death, Inflammation, and Pyroptosis","volume":"38","author":"Kesavardhana","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1038\/s41467-020-16143-6","article-title":"Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection","volume":"11","author":"Beckwith","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/eji.201141548","article-title":"Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis","volume":"42","author":"Dorhoi","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.2174\/1568026617666170130111324","article-title":"Model Systems for Pulmonary Infectious Diseases: Paradigms of Anthrax and Tuberculosis","volume":"17","author":"Arora","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1126\/science.aau1330","article-title":"Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes","volume":"364","author":"Sandstrom","year":"2019","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"105826","DOI":"10.1016\/j.micpath.2022.105826","article-title":"Wnt5a regulates autophagy in Bacille Calmette-Gu\u00e9rin (BCG)-Infected pulmonary epithelial cells","volume":"173","author":"Chen","year":"2022","journal-title":"Microb. Pathog."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1128\/microbiolspec.BAI-0024-2019","article-title":"Infect and Inject: How Mycobacterium tuberculosis Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1","volume":"7","author":"Tiwari","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1111\/brv.12860","article-title":"The PERKs of mitochondria protection during stress: Insights for PERK modulation in neurodegenerative and metabolic diseases","volume":"97","author":"Almeida","year":"2022","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1002\/jcp.25336","article-title":"PERK Integrates Oncogenic Signaling and Cell Survival during Cancer Development","volume":"231","author":"Bu","year":"2016","journal-title":"J. Cell. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.cmet.2022.02.010","article-title":"The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer","volume":"34","author":"Wang","year":"2022","journal-title":"Cell Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1002\/tox.23861","article-title":"Cadmium-induced pyroptosis is mediated by PERK\/TXNIP\/NLRP3 signaling in SH-SY5Y cells","volume":"38","author":"Li","year":"2023","journal-title":"Environ. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110293","DOI":"10.1016\/j.intimp.2023.110293","article-title":"Endoplasmic reticulum stress promotes caspase-1-dependent acinar cell pyroptosis through the PERK pathway to aggravate acute pancreatitis","volume":"120","author":"Yan","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1879","DOI":"10.1038\/cddis.2015.248","article-title":"ER stress induces NLRP3 inflammasome activation and hepatocyte death","volume":"6","author":"Lebeaupin","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"580593","DOI":"10.3389\/fimmu.2020.580593","article-title":"Gallic Acid Alleviates Gouty Arthritis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis through Enhancing Nrf2 Signaling","volume":"11","author":"Lin","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1039\/C2FO30156C","article-title":"Characterization of polarized THP-1 macrophages and polarizing ability of LPS and food compounds","volume":"4","author":"Chanput","year":"2013","journal-title":"Food Funct."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105564","DOI":"10.1016\/j.micpath.2022.105564","article-title":"Ror2-mediated cholesterol accumulation regulates autophagic activity within BCG-infected macrophages","volume":"167","author":"Zheng","year":"2022","journal-title":"Microb. Pathog."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1038\/s41598-023-29900-6","article-title":"DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs\/NF-\u03baB signaling pathway","volume":"13","author":"Liu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1523\/JNEUROSCI.0718-19.2019","article-title":"Aberrant ER Stress Induced Neuronal-IFN\u03b2 Elicits White Matter Injury Due to Microglial Activation and T-Cell Infiltration after TBI","volume":"40","author":"Sen","year":"2020","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16239\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:21:57Z","timestamp":1760131317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16239"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,12]]},"references-count":49,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216239"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216239","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,12]]}}}