Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages
Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on...
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description | Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy. |
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Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1012543</identifier><identifier>PMID: 39250507</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biology and Life Sciences ; Cell receptors ; Health aspects ; Macrophages ; Medical research ; Medicine and Health Sciences ; Medicine, Experimental ; Patient outcomes ; Physiological aspects ; Pregnancy ; Protein kinases ; Research and Analysis Methods ; Spleen ; Toxoplasma</subject><ispartof>PLoS pathogens, 2024-09, Vol.20 (9), p.e1012543</ispartof><rights>Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2024 Public Library of Science</rights><rights>2024 Wang et al 2024 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c423t-84fd3248d1ddbc4e82dea172e32a349bf2f50c22dadb1742e6425349287e42153</cites><orcidid>0000-0003-2992-6571</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11412541/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11412541/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2915,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39250507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Knoll, Laura J.</contributor><creatorcontrib>Wang, Qing</creatorcontrib><creatorcontrib>Cao, Yining</creatorcontrib><creatorcontrib>Ye, Songyi</creatorcontrib><creatorcontrib>Ding, Maoyuan</creatorcontrib><creatorcontrib>Ge, Wenliang</creatorcontrib><creatorcontrib>Liang, Yuejin</creatorcontrib><creatorcontrib>Chen, Jinling</creatorcontrib><title>Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.</description><subject>Biology and Life Sciences</subject><subject>Cell receptors</subject><subject>Health aspects</subject><subject>Macrophages</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Medicine, Experimental</subject><subject>Patient outcomes</subject><subject>Physiological aspects</subject><subject>Pregnancy</subject><subject>Protein kinases</subject><subject>Research and Analysis Methods</subject><subject>Spleen</subject><subject>Toxoplasma</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqVkt2O0zAQhSMEYpeFN0DIEjdwkdZ_2aRXaLXip2IFiC3X1tSepF4SO8RO1T4Jr4ujltVW4gb5wtbMd47kmZNlLxmdMVGy-Z0fBwftrO8hzhhlvJDiUXbOikLkpSjl4wfvs-xZCHeUSibY5dPsTCx4QQtanme_VwN2fH67_zn_thSfCexsINq7ONj1GDGQ6EncINn4EEk_-Ig6Wu8INGBdKq38zvcthA5I452xNrfOjBoNAbPFIWASYePA6T3xY9S-S55bC6TzZmwhWtcQg9qaEVrSgR58v4EGw_PsSQ1twBfH-yL78eH96vpTfvP14_L66ibXkouYV7I2gsvKMGPWWmLFDQIrOQoOQi7WNa8Lqjk3YNaslBwvJS9Sg1clSs4KcZG9O_j247pDozH9HFrVD7aDYa88WHXacXajGr9VjMlp5Cw5vDk6DP7XiCGqzgaNbQsO_RiUYJTLkpYVTejrA9pAi8q62idLPeHqqmKMc1bJRaJm_6DSMdjZtBqsbaqfCN6eCKb14S42MIaglrff_4P9csrKA5u2EsKA9f1YGFVTBtUxg2rKoDpmMMlePRzpvehv6MQfCT3cug</recordid><startdate>20240909</startdate><enddate>20240909</enddate><creator>Wang, Qing</creator><creator>Cao, Yining</creator><creator>Ye, Songyi</creator><creator>Ding, Maoyuan</creator><creator>Ge, Wenliang</creator><creator>Liang, Yuejin</creator><creator>Chen, Jinling</creator><general>Public Library of Science</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2992-6571</orcidid></search><sort><creationdate>20240909</creationdate><title>Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages</title><author>Wang, Qing ; Cao, Yining ; Ye, Songyi ; Ding, Maoyuan ; Ge, Wenliang ; Liang, Yuejin ; Chen, Jinling</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-84fd3248d1ddbc4e82dea172e32a349bf2f50c22dadb1742e6425349287e42153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Biology and Life Sciences</topic><topic>Cell receptors</topic><topic>Health aspects</topic><topic>Macrophages</topic><topic>Medical research</topic><topic>Medicine and Health Sciences</topic><topic>Medicine, Experimental</topic><topic>Patient outcomes</topic><topic>Physiological aspects</topic><topic>Pregnancy</topic><topic>Protein kinases</topic><topic>Research and Analysis Methods</topic><topic>Spleen</topic><topic>Toxoplasma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Qing</creatorcontrib><creatorcontrib>Cao, Yining</creatorcontrib><creatorcontrib>Ye, Songyi</creatorcontrib><creatorcontrib>Ding, Maoyuan</creatorcontrib><creatorcontrib>Ge, Wenliang</creatorcontrib><creatorcontrib>Liang, Yuejin</creatorcontrib><creatorcontrib>Chen, Jinling</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Qing</au><au>Cao, Yining</au><au>Ye, Songyi</au><au>Ding, Maoyuan</au><au>Ge, Wenliang</au><au>Liang, Yuejin</au><au>Chen, Jinling</au><au>Knoll, Laura J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2024-09-09</date><risdate>2024</risdate><volume>20</volume><issue>9</issue><spage>e1012543</spage><pages>e1012543-</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>39250507</pmid><doi>10.1371/journal.ppat.1012543</doi><tpages>e1012543</tpages><orcidid>https://orcid.org/0000-0003-2992-6571</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Biology and Life Sciences Cell receptors Health aspects Macrophages Medical research Medicine and Health Sciences Medicine, Experimental Patient outcomes Physiological aspects Pregnancy Protein kinases Research and Analysis Methods Spleen Toxoplasma |
title | Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages |
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