Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome

Muir, Roshell; Osbourn, Megan; Dubois, Alice; Doran, Emma; Small, D.; Monahan, Avril; O’Kane, Cecilia; McAllister, Katherine; Fitzgerald, Denise; Kissenpfennig, Adrien; McAuley, Daniel F.; Ingram, Rebecca J.

doi:10.1164/rccm.201410-1782oc

Cited by 102 publications

(86 citation statements)

References 47 publications

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“…However, at the chronic stage in CF lungs, P. aeruginosa forms biofilm and switches to a mucoid phenotype, and the effect of CPI-203 on chronic PA infection warrants careful evaluation in the future. We chose the current dose of 10 6 CFU PAO1 per mouse based on the current literature (26, 27). A dose of 10 7 to 10 8 CFU per mouse needs to be used to achieve LD 50 and at this dose the model is more representative of toxin-induced acute lung injury rather than an acute bacterial infection (28).…”

Section: Discussionmentioning

confidence: 99%

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

et al. 2016

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Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes to pathological inflammation in the setting of abnormal mucosal immunity, and type 17 immunity–driven inflammatory responses may represent a target to block aberrant inflammation in CF. Indeed, transcriptomic analysis of the airway epithelium from CF patients undergoing clinical bronchoscopy revealed upregulation of IL-17 downstream signature genes, implicating a substantial contribution of IL-17–mediated immunity in CF lungs. Bromodomain and extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated inflammation, by mechanisms that include bromodomain-dependent inhibition of acetylated histones at the IL17 locus. Here, we show that, in vitro, BET inhibition potently suppressed Th17 cell responses in explanted CF tissue and inhibited IL-17–driven chemokine production in human bronchial epithelial cells. In an acute P. aeruginosa lung infection murine model, BET inhibition decreased inflammation, without exacerbating infection, suggesting that BET inhibition may be a potential therapeutic target in patients with CF.

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Section: Discussionmentioning

confidence: 99%

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

et al. 2016

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“…IL-17, discussed above as critical for activating epithelial cells, was shown to be derived from newly recruited type 3 innate lymphoid cells (ILC3s) after intrapulmonary delivery of Escherichia coli lipopolysaccharide (17), Pseudomonas aeruginosa (17), or K. pneumoniae (18) to mice. The characteristics of ILC3s in the lungs are only beginning to be defined (17). During Klebsiella pneumonia, the recruitment of ILC3s required monocyte-derived TNF-α, which may stimulate lung epithelial cells to synthesize the ILC3-recruiting chemokine CCL20 (18).…”

Section: Advances In Immune Resistancementioning

confidence: 99%

Pathogenesis of severe pneumonia

Mizgerd

2017

Current Opinion in Pulmonary Medicine

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Purpose of review Pneumonia is a common disease that becomes severe in a subset of patients, dependent on host biology including mechanisms of immune resistance and tissue resilience. This review emphasizes discoveries in pneumonia biology from 2016, highlighting questions and directions that are especially pressing or newly emerging. Recent findings Novel cell-cell interactions mediating innate immune responses against microbes in the lung have been elucidated, between distinct leukocyte sub-types as well as between leukocytes and the structural cells of the lung. Adaptive immunity has received growing attention for determining the outcome of pneumonia, particularly the lung resident memory cells that arise from repeated prior respiratory infections and direct heterotypic recall responses. New tissue resilience components have been identified that contribute to anti-inflammatory, pro-resolution, tissue-protective, and reparative regeneration pathways in the infected lung. Summary Recent findings will direct research into fundamental mechanisms of lung protection. Over the longer term, manipulating these pathways has implications for clinical practice, as strategies to bolster resistance and resilience have potential to ameliorate severe pneumonia.

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“…ILC3s are perhaps the most relevant to pneumonia biology and acute pulmonary inflammation, particularly with regards to their influence on IL-17-mediated defense. ILC3s are a prominent source of this cytokine in response to multiple microbial stimuli in the lungs, including P. aeruginosa (31,347), K. pneumoniae (548), and LPS (347). Similarly, IL-22, often associated with Th17 biology and IL-17-dependent lung immunity (23), has been shown to derive from ILC3 cells during pneumococcal pneumonia (510).…”

Section: Innate Lymphocytesmentioning

confidence: 99%

Integrative Physiology of Pneumonia

Quinton

Walkey

Mizgerd

2018

Physiological Reviews

205

203

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Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and inflammation is damaging. Intercellular and interorgan signaling networks coordinate these actions to fight infection and protect the tissue. Cells residing in the lung initiate and steer these responses, with additional immunity effectors recruited from the bloodstream. Responses of extrapulmonary tissues, including the liver, bone marrow, and others, are essential to resistance and resilience. Responses in the lung and extrapulmonary organs can also be counterproductive and drive acute and chronic comorbidities after respiratory infection. This review discusses cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lung injury, chronic pulmonary disease, and adverse extrapulmonary sequelae. Pneumonia should no longer be perceived as simply an acute infection of the lung. Pneumonia susceptibility reflects ongoing and poorly understood chronic conditions, and pneumonia results in diverse and often persistent deleterious consequences for multiple physiological systems.

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Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome

Cited by 102 publications

References 47 publications

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

Pathogenesis of severe pneumonia

Integrative Physiology of Pneumonia

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