{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T12:18:39Z","timestamp":1777033119638,"version":"3.51.4"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Neurobrucellosis is a chronic complication of human brucellosis that is caused by the presence of <jats:italic>Brucella<\/jats:italic> spp in the central nervous system (CNS) and the inflammation play a key role on the pathogenesis. Doxycycline (Dox) is a widely used antibiotic that induces apoptosis of bacteria-infected\u00a0cells. However, the\u00a0mechanisms of <jats:italic>Brucella<\/jats:italic> inhibition of microglial apoptosis and Dox induction of apoptosis are\u00a0still\u00a0poorly\u00a0understood. In this study, we found\u00a0that <jats:italic>Brucella suis<\/jats:italic> S2 strain (<jats:italic>B. suis<\/jats:italic> S2) increased calreticulin (CALR) protein levels and inhbited HMC3 cell apoptosis. Hence, we constructed two HMC3 cell line variants, one with stable overexpression (HMC3-CALR) and one with low expression of CALR (HMC3-sh-CALR). CALR was found to decrease levels of p-JNK and p-p53 proteins, as well as suppress apoptosis in HMC3 cells. These findings suggest that CALR suppresses apoptosis by inhibiting the JNK\/p53 signaling pathway. Next, we treated HMC3, HMC3-CALR and HMC3-sh-CALR cell lines with <jats:italic>B. suis<\/jats:italic> S2 or Dox. Our results demonstrate that <jats:italic>B. suis<\/jats:italic> S2 restrains the JNK\/p53 signaling pathway to inhibit HMC3 cell\u00a0apoptosis <jats:italic>via<\/jats:italic> increasing CALR protein expression, while Dox plays the opposite role. Finally, we treated <jats:italic>B. suis<\/jats:italic> S2-infected HMC3 cells with Dox. Our results confirm that Dox induces JNK\/p53-dependent apoptosis\u00a0in <jats:italic>B. suis<\/jats:italic> S2-infected HMC3 cells through inhibition of CALR protein expression. Taken together, these results reveal that CALR and the JNK\/p53 signaling pathway may serve as novel therapeutic\u00a0targets for treatment of neurobrucellosis.<\/jats:p>","DOI":"10.3389\/fcimb.2021.640847","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T05:29:02Z","timestamp":1619587742000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Doxycycline Induces Apoptosis of Brucella Suis S2 Strain-Infected HMC3 Microglial Cells by Activating Calreticulin-Dependent JNK\/p53 Signaling Pathway"],"prefix":"10.3389","volume":"11","author":[{"given":"Zhao","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanbai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenhai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2016.00030","article-title":"Establishment of Chronic Infection: Brucella\u2019s Stealth Strategy","volume":"6","author":"Ahmed","year":"2016","journal-title":"Front. 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