Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke
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{"title"=>"Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke", "type"=>"journal", "authors"=>[{"first_name"=>"Matthias W.", "last_name"=>"Sieber", "scopus_author_id"=>"13613372400"}, {"first_name"=>"Nadine", "last_name"=>"Jaenisch", "scopus_author_id"=>"26657986900"}, {"first_name"=>"Martin", "last_name"=>"Brehm", "scopus_author_id"=>"55543815100"}, {"first_name"=>"Madlen", "last_name"=>"Guenther", "scopus_author_id"=>"36131382800"}, {"first_name"=>"Bettina", "last_name"=>"Linnartz-Gerlach", "scopus_author_id"=>"55544988800"}, {"first_name"=>"Harald", "last_name"=>"Neumann", "scopus_author_id"=>"7402241146"}, {"first_name"=>"Otto W.", "last_name"=>"Witte", "scopus_author_id"=>"35592935100"}, {"first_name"=>"Christiane", "last_name"=>"Frahm", "scopus_author_id"=>"36947208000"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"368044684", "sgr"=>"84871855675", "pmid"=>"23301011", "scopus"=>"2-s2.0-84871855675", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0052982", "issn"=>"19326203"}, "id"=>"11a17a11-03b3-34de-a440-c3741b72a18e", "abstract"=>"Background: Abstract Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis Methods and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. and Results: As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFa, IL-1a and IL-1b, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1a) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on Conclusions: the lesion size was observed. Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.", "link"=>"http://www.mendeley.com/research/attenuated-inflammatory-response-triggering-receptor-expressed-myeloid-cells-2-trem2-knockout-mice-f", "reader_count"=>64, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>1, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>1, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Engineering"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>12, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>9, "Neuroscience"=>15, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>15}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}, "Unspecified"=>{"Unspecified"=>4}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>3, "Japan"=>1, "United Kingdom"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/278961/Figure_S1.tif", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/279041/Table_S1.doc"], "description"=>"<div><h3>Background</h3><p>Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear.</p> <h3>Methods and Results</h3><p>As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed.</p> <h3>Conclusions</h3><p>Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.</p> </div>", "links"=>[], "tags"=>["attenuated", "inflammatory", "triggering", "receptor", "expressed", "myeloid", "cells", "knock-out", "mice", "stroke"], "article_id"=>115007, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/Attenuated_Inflammatory_Response_in_Triggering_Receptor_Expressed_on_Myeloid_Cells_2_TREM2_Knock_Out_Mice_following_Stroke__/115007", "title"=>"Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-03 01:23:27"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/512908/Figure_1.tif"], "description"=>"<p><b>A.</b> Gene transcripts for TREM2 were determined at 6 h, 12 h, 24 h, 2 d, 7 d and 28 d after stroke in the ipsilateral ischemic hemisphere of C57BL/6 mice. TREM2 was up-regulated at 7 d and 28 d after stroke. Data are displayed as mean ± s.e.m. (ratio ipsi vs. contra), n = 4 each, ***p≤0.001. <b>B.</b> TREM2 gene transcripts were determined at 12 h, 7 d and 28 d after stroke (MCAO) as well as after sham procedure (Sham) in TREM2-KO mice (KO) and littermate controls (WT). Increased TREM2 gene transcription was detected in the ischemic hemisphere of littermate controls (WT MCAO ipsi) at 7 d and 28 d. No increased gene transcripts for TREM2 were observed after stroke in littermate controls at the contralateral side (WT MCAO contra) and following sham procedure (WT Sham). TREM2-KO mice (KO) did not show any TREM2 gene transcription. <b>C.</b> Gene transcripts of cytokines were determined after stroke (MCAO) as well as after sham procedure (Sham) in TREM2-KO mice (KO) and littermate controls (WT). A strong up-regulation of pro-inflammatory cytokines (TNFα, IL-1α, IL-1β and IL-6) was observed 12 h after stroke. A reduced gene transcription of TNFα, IL-1α and IL-1β was observed in TREM2-KO (KO MCAO ipsi) compared to littermate control mice (WT MCAO ipsi) at 7 d after stroke. No differences in cytokine gene transcription were revealed between TREM2-KO mice (KO MCAO ipsi) and littermate controls (WT MCAO ipsi) at 12 h and at 28 d. No increased cytokine expression was observed after stroke in littermate controls at the contralateral side (contra) and in sham operated mice (Sham). Bars represent mean ± s.e.m. (mRNA copies per 1,000 Gapdh), sham: n = 3 each and MCAO: n = 5/6 each, WT ipsi vs. WT contra <sup>#</sup>p≤0.05, <sup>##</sup>p≤0.01, WT ipsi vs. KO ipsi *p≤0.05, **p≤0.01, ***p≤0.001.</p>", "links"=>[], "tags"=>["trem2", "pro-inflammatory", "cytokine", "transcripts", "trem2-ko", "mice"], "article_id"=>183387, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Expression_of_TREM2_and_pro_inflammatory_cytokine_transcripts_in_C57BL_6_and_TREM2_KO_mice_after_stroke_/183387", "title"=>"Expression of TREM2 and pro-inflammatory cytokine transcripts in C57BL/6 and TREM2-KO mice after stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-03 00:56:27"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/513040/Figure_2.tif"], "description"=>"<p><b>A.</b> Post-ischemic Iba1 positive cells (green) displayed the typical activated amoeboid phenotype in the glial scar and infarct core at 7 d and 28 d in WT mice, whereas they remained in a ramified phenotype in TREM2-KO mice. Nuclei of cells counterstained with DAPI (for a better distinction the color was changed to red). Scale bar 20 µm. <b>B.</b> Fewer Iba1 positive activated microglial cells were revealed in the glial scar of TREM2-KO mice (KO) at 7 d following stroke compared to littermate controls (WT). Bars represent mean ± s.e.m., n = 5/6 each, WT ipsi vs. KO ipsi ***p≤0.001. <b>C.</b> Gene transcripts for Iba1 and CD68 were determined at 12 h, 7 d and 28 d after stroke in TREM2-KO mice (KO) and littermate controls (WT). Attenuated gene transcription of Iba1 and CD68 was observed 7 d after stroke in TREM2-KO (KO) mice compared to control (WT) mice. Bars represent mean ± s.e.m. (mRNA copies per 1,000 Gapdh), n = 5/6 each, WT ipsi vs. KO ipsi *p≤0.05 (Iba1), <sup>+</sup>p≤0.05 (CD68).</p>", "links"=>[], "tags"=>["microglial", "activation", "trem2-ko", "mice"], "article_id"=>183528, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Decreased_microglial_activation_in_TREM2_KO_mice_after_stroke_/183528", "title"=>"Decreased microglial activation in TREM2-KO mice after stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-03 00:58:48"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/513183/Figure_3.tif"], "description"=>"<p><b>A.</b> The mRNAs for the chemokines CCL3, CCL2 and CCL5 were increased following stroke in littermate controls (WT) as well as in TREM2-KO mice, with a peak at 12 h for CCL3 and CCL2 and at 7 d for CCL5. Reduced gene transcription of CCL3 and CCL2 was observed at 7 d after stroke in TREM2-KO mice compared to littermate controls. No increased chemokine expression was observed after stroke in littermate controls at the contralateral side and in sham-operated mice. <b>B.</b> Gene transcripts of chemokine receptors were increased after stroke, with a peak at 12 h for CCR1 and at 7 d for CCR2, CCR5 and CX3CR1. Chemokine receptor CX3CR1 expression was attenuated following stroke in TREM2-KO mice. Post-ischemic expression of chemokine receptors was unchanged in littermate controls at the contralateral side and in sham-operated mice. Bars represent mean ± s.e.m. (mRNA copies per 1,000 Gapdh), sham: n = 3 each and MCAO: n = 5/6 each, WT ipsi vs. WT contra <sup>#</sup>p≤0.05, <sup>##</sup>p≤0.01, <sup>###</sup>p≤0.001, WT ipsi vs. KO ipsi *p≤0.05, **p≤0.01.</p>", "links"=>[], "tags"=>["chemokine", "receptor", "transcription", "trem2-ko", "mice"], "article_id"=>183663, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Decreased_chemokine_and_chemokine_receptor_gene_transcription_in_TREM2_KO_mice_after_stroke_/183663", "title"=>"Decreased chemokine and chemokine receptor gene transcription in TREM2-KO mice after stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-03 01:01:03"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/513385/Figure_4.tif"], "description"=>"<p><b>A.</b> CD3-positive T-cells invaded the infarct core at 7 d and 28 d following stroke. Increased numbers of CD3-positive T-cells were visible in the infarct core 28 d after stroke in littermate controls, but not in TREM2-KO mice. Scale bar 50 µm. <b>B.</b> Fewer CD3-positive T-cells were detected 28 d after stroke in TREM2-KO mice compared to their littermate controls. Bars represent mean ± s.e.m, n = 3 each, WT ipsi vs. KO ipsi *p≤0.05.</p>", "links"=>[], "tags"=>["cd3-positive", "t-cells", "trem2-ko", "mice"], "article_id"=>183872, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Fewer_CD3_positive_T_cells_in_TREM2_KO_mice_after_stroke_/183872", "title"=>"Fewer CD3-positive T-cells in TREM2-KO mice after stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-03 01:04:32"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/513470/Figure_5.tif"], "description"=>"<p>Infarct volumes of TREM2-KO and littermate control mice were analyzed at 7 d and 28 d based on Map2 immunohistochemistry. TREM2-KO mice and littermate control mice showed the same relative loss in Map2 immunostaining as a sign of tissue injury. Box and whisker plots represent mean ± s.e.m. (mm<sup>3</sup> injured tissue vs. ipsilateral hemisphere in %), n = 9–14 each.</p>", "links"=>[], "tags"=>["trem2-ko", "mice"], "article_id"=>183960, "categories"=>["Molecular Biology", "Biotechnology", "Neuroscience", "Immunology"], "users"=>["Matthias W. Sieber", "Nadine Jaenisch", "Martin Brehm", "Madlen Guenther", "Bettina Linnartz-Gerlach", "Harald Neumann", "Otto W. Witte", "Christiane Frahm"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0052982.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_No_change_in_brain_tissue_injury_in_TREM2_KO_mice_after_stroke_/183960", "title"=>"No change in brain tissue injury in TREM2-KO mice after stroke.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-03 01:06:00"}

PMC Usage Stats | Further Information

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Relative Metric

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