Bhlhe40 is an essential repressor of IL-10 during <i>Mycobacterium tuberculosis</i> infection

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.

doi:10.1084/jem.20171704

Cited by 104 publications

(156 citation statements)

References 59 publications

(95 reference statements)

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“…15 In contrast, IL-10 production by pulmonary PMNs was actively repressed during Mycobacterium tuberculosis. 55 In this study, we did not detect an upregulation in IL-10 production by PMNs in response to S. pneumoniae infection in WT mice either in vivo during lung challenge or in vitro in response to direct bacterial infection. Further, we were unable to detect an increase in IL-10 mRNA in PMNs isolated from human donors in response to stimulation with S. pneumoniae.…”

Section: Discussioncontrasting

confidence: 68%

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Siwapornchai

Lee

Tchalla

et al. 2020

Journal of Leukocyte Biology

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Polymorphonuclear leukocytes (PMNs) are crucial for initial control of Streptococcus pneumoniae (pneumococcus) lung infection; however, as the infection progresses their persistence in the lungs becomes detrimental. Here we explored why the antimicrobial efficacy of PMNs declines over the course of infection. We found that the progressive inability of PMNs to control infection correlated with phenotypic differences characterized by a decrease in CD73 expression, an enzyme required for production of extracellular adenosine (EAD). EAD production by CD73 was crucial for the ability of both murine and human PMNs to kill S. pneumoniae. In exploring the mechanisms by which CD73 controlled PMN function, we found that CD73 mediated its antimicrobial activity by inhibiting IL‐10 production. PMNs from wild‐type mice did not increase IL‐10 production in response to S. pneumoniae; however, CD73−/− PMNs up‐regulated IL‐10 production upon pneumococcal infection in vitro and during lung challenge. IL‐10 inhibited the ability of WT PMNs to kill pneumococci. Conversely, blocking IL‐10 boosted the bactericidal activity of CD73−/− PMNs as well as host resistance of CD73−/− mice to pneumococcal pneumonia. CD73/IL‐10 did not affect apoptosis, bacterial uptake, and intracellular killing or production of antimicrobial neutrophil elastase and myeloperoxidase. Rather, inhibition of IL‐10 production by CD73 was important for optimal reactive oxygen species (ROS) production by PMNs. ROS contributed to PMN antimicrobial function as their removal or detoxification impaired the ability of PMNs to efficiently kill S. pneumoniae. This study demonstrates that CD73 controls PMN antimicrobial phenotype during S. pneumoniae infection.

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Section: Discussioncontrasting

confidence: 68%

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Siwapornchai

Lee

Tchalla

et al. 2020

Journal of Leukocyte Biology

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“…27 BHLHE40 also play important roles in inflammatory diseases. 28 In autoimmune neuroinflammation, BHLHE40 in Th cells contributes to disease progression. 28 In autoimmune neuroinflammation, BHLHE40 in Th cells contributes to disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…During Mycobacterium tuberculosis infection, BHLHE40 is indispensable to resistance to bacterial infection by repressing IL-10 expression in both T cells and myeloid cells. 28 In autoimmune neuroinflammation, BHLHE40 in Th cells contributes to disease progression. [29][30][31] In colitis model and Toxoplasma gondii infection model, BHLHE40 served as a molecular switch in determining the balance between the inflammatory cytokine IFN-γ and the anti-inflammatory cytokine IL-10 in Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis

Teng

Zhao

et al. 2019

The FASEB Journal

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BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pyloriinfected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4 + T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

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“…IL‐10, a cytokine with anti‐inflammatory properties, can be produced by many immune cells including macrophages, B cells, natural killer cells, and nearly all T cell subsets 15 . Although IL‐10 is considered to protect tissues from damage during inflammatory reactions, 16 overexpression of IL‐10 reportedly increased the pathogen burden and exacerbation of infection 17 . A previous study reported that neutralization of IL‐10 may lead to better control of tuberculosis 18 .…”

Section: Discussionmentioning

confidence: 99%

Immune‐related factors associated with pneumonia in 127 children with coronavirus disease 2019 in Wuhan

Deng

Xiong

et al. 2020

Pediatric Pulmonology

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Objective Information regarding the association of immune‐related factors with pneumonia in children with coronavirus disease 2019 (COVID‐19) is scarce. This study aims to summarize the immune‐related factors and their association with pneumonia in children with COVID‐19. Methods Children with COVID‐19 at Wuhan Children's Hospital from 28 January to 12 March 2020 were enrolled. Pneumonia due to causes other than COVID‐19 were excluded. The clinical and laboratory information including routine blood tests, blood biochemistry, lymphocyte subsets, immunoglobulins, cytokines, and inflammatory factors were analyzed retrospectively in 127 patients. Normal ranges and mean values of laboratory markers were applied as parameters for logistic regression analyses of their association with pneumonia. Results In nonintensive care unit patients, 48.8% and 22.4% of patients had increased levels of procalcitonin and hypersensitive C‐reactive protein (hs‐CRP) respectively. A total 12.6% and 18.1% of patients had decreased levels of immunoglobulin A (IgA) and interleukin 10 (IL‐10), respectively. Approximately 65.8% of patients had pneumonia. These patients had decreased levels of globulin (odds ratio [OR], 3.13; 95% confidence interval [CI] 1.41‐6.93; P = .005), IgA (OR, 4.00; 95% CI, 1.13‐14.18; P = .032), and increased levels of hs‐CRP (OR, 3.14; 95% CI, 1.34‐7.36; P = .008), procalcitonin (OR, 3.83; 95% CI, 2.03‐7.24; P < .001), IL‐10 (OR, 7.0; 95% CI, 1.59‐30.80; P = .010), and CD4+ CD25+ T lymphocyte less than 5.0% (OR, 1.93; 95% CI, 1.04‐3.61; P = 0.038). Conclusion Decreased IgA and CD4+ CD25+ T lymphocyte percentage, and increased hs‐CRP, procalcitonin, and IL‐10 were associated with pneumonia, suggesting that the immune‐related factors may participate in the pathogenesis of pneumonia in children with COVID‐19.

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

Cited by 104 publications

References 59 publications

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis

Immune‐related factors associated with pneumonia in 127 children with coronavirus disease 2019 in Wuhan

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