{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:42:57Z","timestamp":1791726177975,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Project of National Natural Science Foundation of China","award":["32272906"],"award-info":[{"award-number":["32272906"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor \u03b1 (TNF-\u03b1), interleukin-1\u03b2 (IL-1\u03b2) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-\u03b1 and IL-\u03b2 and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses.<\/jats:p>","DOI":"10.3390\/ijms231911218","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T23:13:27Z","timestamp":1664147607000},"page":"11218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model"],"prefix":"10.3390","volume":"23","author":[{"given":"Bei","family":"Zhou","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qilong","family":"Xu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Guo","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Lv","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2894-8560","authenticated-orcid":false,"given":"Jiangchao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3320-2381","authenticated-orcid":false,"given":"Yulan","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1056\/NEJMra021333","article-title":"Medical progress: The Pathophysiology and Treatment of Sepsis","volume":"348","author":"Hotchkiss","year":"2003","journal-title":"N. 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