Trichloroethene metabolite dichloroacetyl chloride induces apoptosis and compromises phagocytosis in Kupffer Cells: Activation of inflammasome and MAPKs
Exposure to trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the development of several autoimmune diseases, including autoimmune hepatitis (AIH). However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichlo...
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| description | Exposure to trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the development of several autoimmune diseases, including autoimmune hepatitis (AIH). However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichloroacetyl chloride (DCAC), one of the reactive metabolites of TCE with strong acylating capability, can elicit an autoimmune response at much lower dose than TCE in female MRL+/+ mice. Furthermore, Kupffer cells (KCs), the liver resident macrophages, are crucial for hepatic homeostasis, but can also participate in the immunopathogenesis of AIH. However, contribution of KCs in TCE-mediated AIH and the underlying mechanisms are not understood. We hypothesized that increased apoptosis and delayed clearance of apoptotic bodies, due to compromised KC function, will result in the breakdown of self-tolerance, autoimmunity, and ultimately AIH. Therefore, using an in vitro model of immortalized mouse KCs, we investigated the contribution of DCAC in TCE-mediated AIH. KCs were treated with different concentrations of DCAC and apoptosis was measured by Annexin V and PI staining. Also, the impact of DCAC on phagocytic potential of KCs was evaluated. Furthermore, markers of inflammasome (NLRP3 and caspase1) were analyzed by real-time PCR and Western blot analysis. DCAC treatment resulted in significantly increased early and late-stage apoptosis, accompanied with inflammasome activation (NLRP3 increases). DCAC treatment resulted in decreased phagocytic function of KCs in a dose-dependent manner, with reduced MFG-E8 levels (phagocytotic function). Furthermore, DCAC exposure led to induction of phos-ERK and phos-AKT signaling. These findings suggest that DCAC induces apoptosis and inflammasome activation, while compromising the phagocytic function of KCs. Our data support that increased apoptosis and impaired KC function by DCAC could be contributory to TCE-mediated AIH. |
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However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichloroacetyl chloride (DCAC), one of the reactive metabolites of TCE with strong acylating capability, can elicit an autoimmune response at much lower dose than TCE in female MRL+/+ mice. Furthermore, Kupffer cells (KCs), the liver resident macrophages, are crucial for hepatic homeostasis, but can also participate in the immunopathogenesis of AIH. However, contribution of KCs in TCE-mediated AIH and the underlying mechanisms are not understood. We hypothesized that increased apoptosis and delayed clearance of apoptotic bodies, due to compromised KC function, will result in the breakdown of self-tolerance, autoimmunity, and ultimately AIH. Therefore, using an in vitro model of immortalized mouse KCs, we investigated the contribution of DCAC in TCE-mediated AIH. KCs were treated with different concentrations of DCAC and apoptosis was measured by Annexin V and PI staining. Also, the impact of DCAC on phagocytic potential of KCs was evaluated. Furthermore, markers of inflammasome (NLRP3 and caspase1) were analyzed by real-time PCR and Western blot analysis. DCAC treatment resulted in significantly increased early and late-stage apoptosis, accompanied with inflammasome activation (NLRP3 increases). DCAC treatment resulted in decreased phagocytic function of KCs in a dose-dependent manner, with reduced MFG-E8 levels (phagocytotic function). Furthermore, DCAC exposure led to induction of phos-ERK and phos-AKT signaling. These findings suggest that DCAC induces apoptosis and inflammasome activation, while compromising the phagocytic function of KCs. Our data support that increased apoptosis and impaired KC function by DCAC could be contributory to TCE-mediated AIH.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0210200</identifier><identifier>PMID: 30596806</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; AKT protein ; Animals ; Annexin V ; Antigen presentation ; Apoptosis ; Apoptosis - drug effects ; Autoimmune diseases ; Biology and Life Sciences ; Chlorides ; Contaminants ; Cytokines ; Cytotoxicity ; Disease ; Dose-Response Relationship, Drug ; Enzyme Activation - drug effects ; Exposure ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Female ; Hepatitis ; Hepatocytes ; Homeostasis ; Immunoglobulins ; Immunological tolerance ; Immunopathogenesis ; Inflammasomes ; Inflammasomes - metabolism ; Inflammation ; Kinases ; Kupffer cells ; Kupffer Cells - metabolism ; Kupffer Cells - pathology ; Liver ; Lymphocytes ; Macrophages ; MAP Kinase Signaling System - drug effects ; Medicine and Health Sciences ; Metabolites ; Mice ; Occupational exposure ; Oxidative stress ; Pathogenesis ; Pathology ; Phagocytes ; Phagocytosis ; Phagocytosis - drug effects ; Proteins ; Rodents ; Trichloroethylene ; Trichloroethylene - pharmacology ; Trichloroethylene - toxicity ; Variance analysis</subject><ispartof>PloS one, 2018-12, Vol.13 (12), p.e0210200</ispartof><rights>2018 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Wang et al 2018 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-b4049a4dca3f647bb3c37809915bd6e6bfa82f6df62c6e8be6f52d2034d791313</citedby><cites>FETCH-LOGICAL-c526t-b4049a4dca3f647bb3c37809915bd6e6bfa82f6df62c6e8be6f52d2034d791313</cites><orcidid>0000-0002-0387-0584</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/PMC6312261/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312261/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2919,23857,27915,27916,53782,53784,79361,79362</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30596806$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Singla, Dinender K</contributor><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Wang, Gangduo</creatorcontrib><creatorcontrib>Ansari, G A Shakeel</creatorcontrib><creatorcontrib>Khan, M Firoze</creatorcontrib><title>Trichloroethene metabolite dichloroacetyl chloride induces apoptosis and compromises phagocytosis in Kupffer Cells: Activation of inflammasome and MAPKs</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Exposure to trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the development of several autoimmune diseases, including autoimmune hepatitis (AIH). However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichloroacetyl chloride (DCAC), one of the reactive metabolites of TCE with strong acylating capability, can elicit an autoimmune response at much lower dose than TCE in female MRL+/+ mice. Furthermore, Kupffer cells (KCs), the liver resident macrophages, are crucial for hepatic homeostasis, but can also participate in the immunopathogenesis of AIH. However, contribution of KCs in TCE-mediated AIH and the underlying mechanisms are not understood. We hypothesized that increased apoptosis and delayed clearance of apoptotic bodies, due to compromised KC function, will result in the breakdown of self-tolerance, autoimmunity, and ultimately AIH. Therefore, using an in vitro model of immortalized mouse KCs, we investigated the contribution of DCAC in TCE-mediated AIH. KCs were treated with different concentrations of DCAC and apoptosis was measured by Annexin V and PI staining. Also, the impact of DCAC on phagocytic potential of KCs was evaluated. Furthermore, markers of inflammasome (NLRP3 and caspase1) were analyzed by real-time PCR and Western blot analysis. DCAC treatment resulted in significantly increased early and late-stage apoptosis, accompanied with inflammasome activation (NLRP3 increases). DCAC treatment resulted in decreased phagocytic function of KCs in a dose-dependent manner, with reduced MFG-E8 levels (phagocytotic function). Furthermore, DCAC exposure led to induction of phos-ERK and phos-AKT signaling. These findings suggest that DCAC induces apoptosis and inflammasome activation, while compromising the phagocytic function of KCs. Our data support that increased apoptosis and impaired KC function by DCAC could be contributory to TCE-mediated AIH.</description><subject>Activation</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Annexin V</subject><subject>Antigen presentation</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autoimmune diseases</subject><subject>Biology and Life Sciences</subject><subject>Chlorides</subject><subject>Contaminants</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Disease</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activation - drug effects</subject><subject>Exposure</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Female</subject><subject>Hepatitis</subject><subject>Hepatocytes</subject><subject>Homeostasis</subject><subject>Immunoglobulins</subject><subject>Immunological tolerance</subject><subject>Immunopathogenesis</subject><subject>Inflammasomes</subject><subject>Inflammasomes - 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However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichloroacetyl chloride (DCAC), one of the reactive metabolites of TCE with strong acylating capability, can elicit an autoimmune response at much lower dose than TCE in female MRL+/+ mice. Furthermore, Kupffer cells (KCs), the liver resident macrophages, are crucial for hepatic homeostasis, but can also participate in the immunopathogenesis of AIH. However, contribution of KCs in TCE-mediated AIH and the underlying mechanisms are not understood. We hypothesized that increased apoptosis and delayed clearance of apoptotic bodies, due to compromised KC function, will result in the breakdown of self-tolerance, autoimmunity, and ultimately AIH. Therefore, using an in vitro model of immortalized mouse KCs, we investigated the contribution of DCAC in TCE-mediated AIH. KCs were treated with different concentrations of DCAC and apoptosis was measured by Annexin V and PI staining. Also, the impact of DCAC on phagocytic potential of KCs was evaluated. Furthermore, markers of inflammasome (NLRP3 and caspase1) were analyzed by real-time PCR and Western blot analysis. DCAC treatment resulted in significantly increased early and late-stage apoptosis, accompanied with inflammasome activation (NLRP3 increases). DCAC treatment resulted in decreased phagocytic function of KCs in a dose-dependent manner, with reduced MFG-E8 levels (phagocytotic function). Furthermore, DCAC exposure led to induction of phos-ERK and phos-AKT signaling. These findings suggest that DCAC induces apoptosis and inflammasome activation, while compromising the phagocytic function of KCs. Our data support that increased apoptosis and impaired KC function by DCAC could be contributory to TCE-mediated AIH.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30596806</pmid><doi>10.1371/journal.pone.0210200</doi><orcidid>https://orcid.org/0000-0002-0387-0584</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Activation AKT protein Animals Annexin V Antigen presentation Apoptosis Apoptosis - drug effects Autoimmune diseases Biology and Life Sciences Chlorides Contaminants Cytokines Cytotoxicity Disease Dose-Response Relationship, Drug Enzyme Activation - drug effects Exposure Extracellular Signal-Regulated MAP Kinases - metabolism Female Hepatitis Hepatocytes Homeostasis Immunoglobulins Immunological tolerance Immunopathogenesis Inflammasomes Inflammasomes - metabolism Inflammation Kinases Kupffer cells Kupffer Cells - metabolism Kupffer Cells - pathology Liver Lymphocytes Macrophages MAP Kinase Signaling System - drug effects Medicine and Health Sciences Metabolites Mice Occupational exposure Oxidative stress Pathogenesis Pathology Phagocytes Phagocytosis Phagocytosis - drug effects Proteins Rodents Trichloroethylene Trichloroethylene - pharmacology Trichloroethylene - toxicity Variance analysis |
| title | Trichloroethene metabolite dichloroacetyl chloride induces apoptosis and compromises phagocytosis in Kupffer Cells: Activation of inflammasome and MAPKs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T06%3A08%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Trichloroethene%20metabolite%20dichloroacetyl%20chloride%20induces%20apoptosis%20and%20compromises%20phagocytosis%20in%20Kupffer%20Cells:%20Activation%20of%20inflammasome%20and%20MAPKs&rft.jtitle=PloS%20one&rft.au=Wang,%20Hui&rft.date=2018-12-31&rft.volume=13&rft.issue=12&rft.spage=e0210200&rft.pages=e0210200-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0210200&rft_dat=%3Cproquest_plos_%3E2161934984%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2161934984&rft_id=info:pmid/30596806&rft_doaj_id=oai_doaj_org_article_e1ca25599d4a430a804bb6785dc465c6&rfr_iscdi=true |