Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection

The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the tran...

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Published inThe Journal of experimental medicine Vol. 215; no. 7; pp. 1823 - 1838
Main Authors Huynh, Jeremy P., Lin, Chih-Chung, Kimmey, Jacqueline M., Jarjour, Nicholas N., Schwarzkopf, Elizabeth A., Bradstreet, Tara R., Shchukina, Irina, Shpynov, Oleg, Weaver, Casey T., Taneja, Reshma, Artyomov, Maxim N., Edelson, Brian T., Stallings, Christina L.
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 02.07.2018
Subjects
Adaptive control
Adaptive Immunity
Animal models
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors - deficiency
Basic Helix-Loop-Helix Transcription Factors - metabolism
CD11c antigen
Clonal deletion
Genetic Loci
Helix-loop-helix proteins (basic)
Homeodomain Proteins - metabolism
Immune system
Immunity, Innate
Infections
Inflammation - pathology
Interleukin 1
Interleukin 10
Interleukin-10 - deficiency
Interleukin-10 - metabolism
Lymphocytes
Lymphocytes - metabolism
Lymphocytes T
Mice
Mice, Inbred C57BL
Models, Biological
Mycobacterium tuberculosis
Myeloid Cells - metabolism
Neutrophils - metabolism
Pathogenesis
Phenotypes
Protein Binding
Repressor Proteins - metabolism
Th1 Cells - metabolism
Transcription factors
Tuberculosis
Tuberculosis - immunology
Tuberculosis - prevention & control
γ-Interferon
Online AccessGet full text
ISSN0022-1007
1540-9538
1540-9538
DOI10.1084/jem.20171704

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Abstract The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40−/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
AbstractList This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection.The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40−/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.Graphical Abstract[Figure]
This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis ( Mtb ) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40 −/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c + cells is sufficient to cause susceptibility to Mtb . Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
The cytokine IL-10 antagonizes pathways that control ( ) infection. Nevertheless, the impact of IL-10 during infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress expression during infection. Loss of Bhlhe40 in mice results in higher expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of in mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c cells is sufficient to cause susceptibility to Bhlhe40 represents the first transcription factor found to be essential during infection to specifically regulate expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in pathogenesis.
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40−/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
Author Kimmey, Jacqueline M.
Artyomov, Maxim N.
Stallings, Christina L.
Schwarzkopf, Elizabeth A.
Shchukina, Irina
Huynh, Jeremy P.
Weaver, Casey T.
Edelson, Brian T.
Jarjour, Nicholas N.
Taneja, Reshma
Shpynov, Oleg
Lin, Chih-Chung
Bradstreet, Tara R.
AuthorAffiliation 1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO
3 JetBrains Research, Saint Petersburg, Russia
5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
AuthorAffiliation_xml – name: 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
– name: 3 JetBrains Research, Saint Petersburg, Russia
– name: 4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
– name: 5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
– name: 1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/29773644$$D View this record in MEDLINE/PubMed
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J.P. Huynh and C.-C. Lin contributed equally to this paper.
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Snippet The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has...
The cytokine IL-10 antagonizes pathways that control ( ) infection. Nevertheless, the impact of IL-10 during infection has been difficult to decipher because...
This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis...
This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis...
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proquest
pubmed
crossref
SourceType Open Access Repository
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Enrichment Source
StartPage 1823
SubjectTerms Adaptive control
Adaptive Immunity
Animal models
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors - deficiency
Basic Helix-Loop-Helix Transcription Factors - metabolism
CD11c antigen
Clonal deletion
Genetic Loci
Helix-loop-helix proteins (basic)
Homeodomain Proteins - metabolism
Immune system
Immunity, Innate
Infections
Inflammation - pathology
Interleukin 1
Interleukin 10
Interleukin-10 - deficiency
Interleukin-10 - metabolism
Lymphocytes
Lymphocytes - metabolism
Lymphocytes T
Mice
Mice, Inbred C57BL
Models, Biological
Mycobacterium tuberculosis
Myeloid Cells - metabolism
Neutrophils - metabolism
Pathogenesis
Phenotypes
Protein Binding
Repressor Proteins - metabolism
Th1 Cells - metabolism
Transcription factors
Tuberculosis
Tuberculosis - immunology
Tuberculosis - prevention & control
γ-Interferon
Title Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection
URI https://www.ncbi.nlm.nih.gov/pubmed/29773644
https://www.proquest.com/docview/2062817970
https://www.proquest.com/docview/2041631747
https://pubmed.ncbi.nlm.nih.gov/PMC6028511
Volume 215
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