Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway
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{"title"=>"Neutrophils promote mycobacterial trehalose dimycolate-induced lung inflammation via the mincle pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Wook Bin", "last_name"=>"Lee", "scopus_author_id"=>"57192440815"}, {"first_name"=>"Ji Seon", "last_name"=>"Kang", "scopus_author_id"=>"55222041200"}, {"first_name"=>"Ji Jing", "last_name"=>"Yan", "scopus_author_id"=>"55467833600"}, {"first_name"=>"Myeong Sup", "last_name"=>"Lee", "scopus_author_id"=>"57051584900"}, {"first_name"=>"Bo Young", "last_name"=>"Jeon", "scopus_author_id"=>"7102161950"}, {"first_name"=>"Sang Nae", "last_name"=>"Cho", "scopus_author_id"=>"7404881228"}, {"first_name"=>"Young Joon", "last_name"=>"Kim", "scopus_author_id"=>"55158701300"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"pui"=>"364837066", "issn"=>"15537366", "isbn"=>"3120100001008", "doi"=>"10.1371/journal.ppat.1002614", "scopus"=>"2-s2.0-84861205868", "pmid"=>"22496642", "sgr"=>"84861205868"}, "id"=>"f8a7a590-e2ec-36fb-a2d4-fa839a822410", "abstract"=>"Trehalose 6,6'-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle⁻/⁻ mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses.", "link"=>"http://www.mendeley.com/research/neutrophils-promote-mycobacterial-trehalose-dimycolateinduced-lung-inflammation-via-mincle-pathway", "reader_count"=>79, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>3, "Researcher"=>18, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>3, "Student > Master"=>11, "Other"=>2, "Student > Bachelor"=>6, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>3, "Researcher"=>18, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>3, "Student > Master"=>11, "Other"=>2, "Student > Bachelor"=>6, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>6, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>45, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemical Engineering"=>1, "Chemistry"=>4, "Computer Science"=>1, "Immunology and Microbiology"=>8}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>45}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>6}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"Canada"=>2, "Korea (South)"=>1, "South Africa"=>1, "Australia"=>1, "India"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/658177"], "description"=>"<p>(A) Levels of phosphorylated Erk, p38, and Jnk in wild-type (WT) and Mincle<sup>−/−</sup> (KO) bone marrow (BM) neutrophils 30 min after TNFα (Con) and TNFα/trehalose dimycolate (TDM) stimulation as determined by immunoblot analysis. (B–C) Neutrophil adherence (B) and F-actin polymerization (C) were measured in C57BL/6 BM neutrophils stimulated with TDM in the presence of PP1 (5 µM), Piceatannol (40 µM), AG490 (25 µM), or U0126 (10 µM). Statistical significance is shown relative to TDM-treated neutrophils. **p<0.01, and ***p<0.001 (D–E) Surface expression of CD11b (B) and CD18 (C) was measured by flow cytometry in WT and Mincle<sup>−/−</sup> BM neutrophils stimulated with TDM for 18 h in the presence of specific inhibitors. Statistical significance is shown relative to TDM-treated WT neutrophils. *p<0.05. Data are expressed as means ± SEM from three independent experiments.</p>", "links"=>[], "tags"=>["syk", "kinase", "tdm-mediated", "neutrophil"], "article_id"=>328652, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_Syk_and_MAP_kinase_during_TDM_mediated_neutrophil_adhesion_/328652", "title"=>"Activation of Syk and MAP kinase during TDM-mediated neutrophil adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:24:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/657811"], "description"=>"<p>(A) Bone marrow (BM) neutrophils from C57BL/6 mice were stimulated with 10 ng/ml LPS or 25 µg/ml trehalose dimycolate (TDM). Mincle mRNA expression was measured by quantitative RT-PCR and normalized to Hprt mRNA levels. Significantly different levels from 0 h are indicated. *p<0.05 and ***p<0.001. (B) Mincle surface expression was determined by flow cytometry. BM neutrophils from WT and Mincle<sup>−/−</sup> mice were stimulated with 25 µg/ml TDM for 18 h and analyzed by flow cytometry. See also <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002614#ppat.1002614.s001\" target=\"_blank\">Figure S1</a>. (C–D) Matrices were injected into mice (s.c.) and harvested after 20 h. Formaldehyde-fixed paraffin-embedded sections were Hematoxylin and eosin stained. (C) Matrices contained non-coated beads with C57BL/6 bone marrow macrophages (BMMs) (left panel) or TDM-coated beads without BMMs (right panel). (D) Matrices containing TDM-coated beads were injected into wild-type (WT, upper panels) or Mincle<sup>−/−</sup> (KO, lower panels) mice with WT BMMs (left panels) or Mincle<sup>−/−</sup> BMMs (right panels). Photomicrographs are representative regions from each section. Scale bars represent 100 µm. (E–F) Ly6G<sup>+</sup> neutrophils (E) or F4/80<sup>+</sup> macrophages (F) adjacent to TDM-coated beads were counted from at least five randomly-selected fields from each stained section. Statistical significance: **p<0.01. Data are representative of at least three independent experiments.</p>", "links"=>[], "tags"=>["recruited", "tdm-coated-beads", "tdm"], "article_id"=>328296, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neutrophils_were_recruited_to_TDM_coated_beads_by_recognition_of_TDM_through_Mincle_/328296", "title"=>"Neutrophils were recruited to TDM-coated-beads by recognition of TDM through Mincle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:18:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/657920"], "description"=>"<p>(A) Firmly-adherent wild-type (WT) and Mincle<sup>−/−</sup> bone marrow (BM) neutrophils were counted after incubation in the presence or absence of 25 µg/ml trehalose dimycolate (TDM). Statistical significance is shown relative to unstimulated control (con) for each group. *p<0.05 and **p<0.01. (B) Firmly-adherent WT and Mincle<sup>−/−</sup> BM neutrophils treated with TNFα and/or TDM for 60 min were imaged by phage-contrast microscopy. Original magnification was 400×. (C) BM neutrophils were cultured on TDM-coated coverslips for 60 min, and F-actin polymerization was monitored by immunofluorescent microscopy (right). Images are representative of three independent experiments. Alexa 568-phalloidin staining was quantified by mean fluorescence intensity (MFI, left). Statistical significance: *p<0.05 and **p<0.01. (D–E) Neutrophil adherence (D) and F-actin polymerization (E) stimulated by TDM, LPS, Pam3CSK4, or peptidoglycan for 18 h (D) or 1 h (E). Statistical significance: *p<0.05 and **p<0.01. Data are expressed as means ± SEM from at least three independent experiments.</p>", "links"=>[], "tags"=>["neutrophil", "adhesion", "f-actin", "polymerization", "mincle"], "article_id"=>328395, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g003", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TDM_induced_neutrophil_adhesion_and_F_actin_polymerization_are_Mincle_dependent_/328395", "title"=>"TDM-induced neutrophil adhesion and F-actin polymerization are Mincle dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:19:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/658349"], "description"=>"<p>Wild-type (WT), Mincle<sup>−/−</sup>, MyD88<sup>−/−</sup>, and double knockout (DKO) bone marrow neutrophils were stimulated with Pam3CSK4 (10 ng/ml) and/or trehalose dimycolate (TDM, 25 µg/ml) for the indicated times (h). Surface expression of CD11b, CD18, and CD62L was analyzed by flow cytometry. Reactive oxygen species (ROS) production was assessed by the oxidation of H<sub>2</sub>DCFDA derivatives as measured with a microplate reader at 485/520 nm and DHR123 as measured by flow cytometry. Statistical significance: *p<0.05. Data are expressed as means ± SEM from at least three independent experiments.</p>", "links"=>[], "tags"=>["tdm", "pam3csk4", "synergistically", "up-regulated", "ros"], "article_id"=>328834, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g006", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Co_stimulation_with_TDM_and_Pam3CSK4_synergistically_up_regulated_CD11b_CD18_expression_and_ROS_production_/328834", "title"=>"Co-stimulation with TDM and Pam3CSK4 synergistically up-regulated CD11b/CD18 expression and ROS production.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:27:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/658464"], "description"=>"<p>Wild-type (WT), Mincle<sup>−/−</sup>, MyD88<sup>−/−</sup>, and Mincle<sup>−/−</sup>MyD88<sup>−/−</sup> (DKO) bone marrow neutrophils were stimulated with Pam3CSK4 (10 ng/ml) and/or trehalose dimycolate (TDM, 25 µg/ml). (A) Firmly-adherent neutrophils were counted after incubation for 6 h with Pam3CSK4 and/or TDM. (B) TNFα production was measured 24 h after stimulation. (C) Mincle expression on neutrophils 18 h after stimulation was measured by flow cytometry. Statistical significance: *p<0.05 and **p<0.01. Data are expressed as means ± SEM from more than three independent experiments.</p>", "links"=>[], "tags"=>["adhesion", "co-stimulation", "correlated", "mincle"], "article_id"=>328944, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_adhesion_and_TNF_945_production_following_co_stimulation_with_TDM_Pam3CSK4_correlated_with_Mincle_expression_/328944", "title"=>"Cell adhesion and TNFα production following co-stimulation with TDM/Pam3CSK4 correlated with Mincle expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:29:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/658078"], "description"=>"<p>(A) Bone marrow (BM) neutrophils from wild-type (WT) and Mincle<sup>−/−</sup> mice were stimulated with 25 µg/ml trehalose dimycolate (TDM). CD11b and CD18 mRNA expression was measured by quantitative RT-PCR. (B) Surface CD11b, CD18, and CD62L levels of control or 18 h TDM stimulated BM neutrophils were quantified by flow cytometry. MFI, mean fluorescence intensity (MFI). Statistical significance: *p<0.05 and **p<0.01. (C) Firmly-adherent neutrophils were counted after incubation in the presence or absence of TDM and were treated with anti-CD11b (M1/70) or control immunoglobulin G (IgG). Statistical significance: *p<0.05 and **p<0.01. Data are expressed as means ± SEM from three independent experiments.</p>", "links"=>[], "tags"=>["tdm-mincle", "signaling", "enhanced", "neutrophil"], "article_id"=>328555, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g004", "stats"=>{"downloads"=>1, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Up_regulated_CD11b_CD18_surface_expression_following_TDM_Mincle_signaling_enhanced_neutrophil_adhesion_/328555", "title"=>"Up-regulated CD11b/CD18 surface expression following TDM-Mincle signaling enhanced neutrophil adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:22:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/658671"], "description"=>"<p>C57BL/6 mice received intravenous injections of Ly6G mAb or IgG control mAb 1 day before trehalose dimycolate (TDM) administration (n = 3 mice/group). After TDM administration (2 or 5 days), lung tissues and peripheral blood were obtained. (A) Whole-lung cells were analyzed using flow cytometry. Statistical significance: *p<0.05 and **p<0.01. (B) Image quantification of relative granuloma areas. Statistical significance: *p<0.05. (C) Hematoxylin and eosin (H&E) staining and Ly6G-immunohistochemical staining of neutrophils in lung tissues. Original magnification was 40×. Scale bars represent 50 µm. (D) TNFα, IL-6, and MCP-1 protein levels from whole-lung homogenates were determined by CBA. (E) Serum TNFα levels in peripheral blood from mice were measured by CBA. Statistical significance: *p<0.05. Data are expressed as means ± SEM from more than three independent experiments.</p>", "links"=>[], "tags"=>["mice", "had", "weakened", "immunity", "tdm-elicited"], "article_id"=>329154, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g009", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neutrophil_depleted_mice_had_weakened_immunity_during_TDM_elicited_inflammation_/329154", "title"=>"Neutrophil-depleted mice had weakened immunity during TDM-elicited inflammation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:32:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/658555"], "description"=>"<p>(A) Viable bacterial numbers in the lungs of wild-type (WT) and Mincle<sup>−/−</sup> mice (n≥4) were determined at the indicated time points following <i>mycobacterium tuberculosis</i> (Mtb) infection. Mean log colony-forming units (CFUs) per lung (±SEM) are shown. (B–E) TNFα (B), IL-6 (C), IFNγ (D), and IL-1β (E) levels were measured in the lungs of WT and Mincle<sup>−/−</sup> mice at the indicated time points following virulent Mtb strain Erdman infection. Statistical significance is shown relative to WT for each group. *p<0.05. (F) Histology of Hematoxylin and eosin (H&E)-stained lung tissues from Mtb-infected WT and Mincle<sup>−/−</sup> mice. Original magnification was 4×. Scale bars represent 500 µm.</p>", "links"=>[], "tags"=>["loads", "cytokine", "levels", "elevated", "lungs", "mice"], "article_id"=>329034, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g008", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bacterial_loads_and_cytokine_levels_are_elevated_in_lungs_from_Mincle_8722_8722_mice_following_Mycobacterium_tuberculosis_infection_/329034", "title"=>"Bacterial loads and cytokine levels are elevated in lungs from Mincle<sup>−/−</sup> mice following <i>Mycobacterium tuberculosis</i> infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:30:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/657685"], "description"=>"<p>Wild-type (WT) and Mincle<sup>−/−</sup> mice were injected intravenously with an oil-in-water emulsion containing TDM. Emulsion without TDM was injected as a vehicle control. Mice were sacrificed at days 0, 1, 2, 5, and 7 post-TDM challenge. (A) Hematoxylin and eosin (H&E)-stained lung histology. Original magnification was 10×. Scale bars represent 100 µm. (B) Lungs from TDM-challenged mice were removed each day and inflammatory intensities were measured by calculating the lung weight index (LWI). n = 4–6 mice per group. Statistical significance: **p<0.01 and ***p<0.001. (C) Identification of leukocyte subsets in lung granulomas by flow cytometry. The number of neutrophils (CD11b<sup>+</sup> Ly6G<sup>+</sup>), monocytes and macrophages (Mono/Macro, CD11b<sup>+</sup> Ly6G<sup>−</sup>), T cells (CD3<sup>+</sup>), and B cells (CD19<sup>+</sup>) are indicated. Statistical significance is shown relative to day 0 for each group. *p<0.05 (in neutrophils) and ΦΦΦp<0.001 (in monocytes and macrophages). (D) Immunohistochemical Ly6G staining of neutrophils. Arrow heads indicate Ly6G+ cells near blood vessels (upper panels). Immunohistochemical F4/80 staining of macrophages. Asterisks indicate individual F4/80+ cells (lower panels). Sections are representative of 4–6 mice per group. Original magnification was 40×. Scale bars represent 50 µm. (E) TNFα, IL-6, and MCP-1 mRNA levels in whole-lung cell homogenates from WT and Mincle<sup>−/−</sup> mice following TDM administration were measured by quantitative RT-PCR. Statistical significance is shown relative to control (con) for each group. *p<0.05, **p<0.01 and ***p<0.001. Data represent means ± SEM from five independent experiments.</p>", "links"=>[], "tags"=>["tdm-induced", "granuloma", "wt"], "article_id"=>328165, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002614.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetics_of_TDM_induced_lung_granuloma_formation_in_WT_and_Mincle_8722_8722_mice_/328165", "title"=>"Kinetics of TDM-induced lung granuloma formation in WT and Mincle<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-05 02:16:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/337515", "https://ndownloader.figshare.com/files/337545", "https://ndownloader.figshare.com/files/337597", "https://ndownloader.figshare.com/files/337639"], "description"=>"<div><p>Trehalose 6,6′-dimycolate (TDM), a cord factor of <em>Mycobacterium tuberculosis</em> (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle<sup>−/−</sup> mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses.</p> </div>", "links"=>[], "tags"=>["neutrophils", "mycobacterial", "trehalose", "dimycolate-induced", "inflammation", "mincle", "pathway"], "article_id"=>126710, "categories"=>["Microbiology", "Immunology"], "users"=>["Wook-bin Lee", "Ji-Seon Kang", "Ji-Jing Yan", "Myeong Sup Lee", "Bo-Young Jeon", "Sang-Nae Cho", "Young-Joon Kim"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002614.s001", "https://dx.doi.org/10.1371/journal.ppat.1002614.s002", "https://dx.doi.org/10.1371/journal.ppat.1002614.s003", "https://dx.doi.org/10.1371/journal.ppat.1002614.s004"], "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Neutrophils_Promote_Mycobacterial_Trehalose_Dimycolate_Induced_Lung_Inflammation_via_the_Mincle_Pathway/126710", "title"=>"Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-04-05 01:51:50"}

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