{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:22:10Z","timestamp":1788477730815,"version":"build-2803163510"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Neutrophils are the most abundant and shortest-lived leukocytes in humans and tight regulation of neutrophil turnover <jats:italic>via<\/jats:italic> constitutive apoptosis is essential for control of infection and resolution of inflammation. Accordingly, aberrant neutrophil turnover is hallmark of many disease states. We have shown in previous work that the intracellular bacterial pathogen <jats:italic>Francisella tularensis<\/jats:italic> markedly prolongs human neutrophil lifespan. This is achieved, in part, by changes in neutrophil gene expression. Still unknown is the contribution of major neutrophil pro-survival signaling cascades to this process. The objective of this study was to interrogate the contributions of ERK and p38 MAP kinase, Class I phosphoinositide 3-kinases (PI3K), AKT, and NF-\u03baB to neutrophil survival in our system. We demonstrate that both ERK2 and p38\u03b1 were activated in <jats:italic>F. tularensis<\/jats:italic>-infected neutrophils, but only p38\u03b1 MAPK was required for delayed apoptosis and the rate of cell death in the absence of infection was unchanged. Apoptosis of both infected and uninfected neutrophils was markedly accelerated by the pan-PI3K inhibitor LY2094002, but AKT phosphorylation was not induced, and neutrophil death was not enhanced by AKT inhibitors. In addition, isoform specific and selective inhibitors revealed a unique role for PI3K\u03b1 in neutrophil survival after infection, whereas only simultaneous inhibition of PI3K\u03b1 and PI3k\u03b4 accelerated death of the uninfected controls. Finally, we show that inhibition of NF-\u03baB triggered rapid death of neutrophil after infection. Thus, we defined roles for p38\u03b1, PI3K\u03b1 and NF-\u03baB delayed apoptosis of <jats:italic>F. tularensis<\/jats:italic>-infected cells and advanced understanding of Class IA PI3K isoform activity in human neutrophil survival.<\/jats:p>","DOI":"10.3389\/fcimb.2022.889290","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T17:23:41Z","timestamp":1657128221000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Neutrophil Survival Signaling During Francisella tularensis Infection"],"prefix":"10.3389","volume":"12","author":[{"given":"Lauren C.","family":"Kinkead","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J.","family":"Krysa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee-Ann H.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/S0014-5793(00)02324-3","article-title":"Molecular Control of Neutrophil Apoptosis","volume":"487","author":"Akgul","year":"2001","journal-title":"FEBS Lett."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109256","article-title":"IL-32gamma Delays Spontaneous Apoptosis of Human Neutrophils Through MCL-1, Regulated Primarily by the P38 MAPK Pathway","volume":"9","author":"Allaeys","year":"2014","journal-title":"PLos One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/ncb1005","article-title":"Inhibition of Caspase-9 Through Phosphorylation at Thr 125 by ERK MAPK","volume":"5","author":"Allan","year":"2003","journal-title":"Nat. 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