Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2

Aoyagi, Tetsuji; Newstead, Michael W.; Zeng, Xianying; Nanjo, Yuta; Peters‐Golden, Marc; Kaku, Mitsuo; Standiford, Theodore J.

doi:10.1371/journal.ppat.1006737

Cited by 51 publications

(67 citation statements)

References 60 publications

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“…Nevertheless, there is also some evidence that inhibiting PGE2 might be detrimental, e.g. resulting in impaired bacterial killing of P. aeruginosa (Aoyagi et al, 2017) exacerbation of OA-induced ARDS by indomethacin in rats (Sharma et al, 2016) and exacerbation of lung neutrophilic inflammation (Felton et al, 2018).…”

Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatementioning

confidence: 99%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

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Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatementioning

confidence: 99%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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show abstract

“…PGE2 signaling triggers hyperplasia of the mammary gland and regulates VEGF induction in breast tumors in mice (53). In addition, EP2 signaling can directly regulate tumor angiogenesis and survival by enhancing the activity of epithelial cells (1,74). It can also regulate hypertrophy and tumor invasion as a response to UV stimulation and induce the growth of skin tumors (57).…”

Section: Ep2 Contributes To Cancer Immunotherapy Resistancementioning

confidence: 99%

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

Sun

2018

Int J Mol Med

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Prostaglandin E2 (PGE2) receptor 2 subtype (EP2), which is a metabolite of arachidonic acid that binds with and regulates cellular responses to PGE2, is associated with numerous physiological and pathological events in a wide range of tissues. As a stimulatory G protein‑coupled receptor, PGE2‑induced EP2 activation can activate adenylate cyclase, leading to increased cytoplasmic cAMP levels and activation of protein kinase A. The EP2 receptor can also activate the glycogen synthase kinase 3β and β‑catenin pathways. The present study aimed to review the roles of the EP2 receptor in tumor development, including immunity, chronic inflammation, angiogenesis, metastasis and multidrug resistance. Furthermore, the involvement of the EP2 receptor signaling pathway in cancer was discussed. Understanding the role and mechanisms of action of the EP2 receptor, and its importance in targeted therapy, may help identify novel methods to improve management of numerous types of cancer.

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“…Infection and Immunity receptor deletion decreases mortality and lung injury in mice with influenza and cytotoxic Pseudomonas aeruginosa pneumonia (39,42). The effects in influenza virus and P. aeruginosa infections are contrary to those observed in L. pneumophila pneumonia.…”

Section: Il-36 Cytokines In Legionella Pneumoniamentioning

confidence: 99%

Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

et al. 2019

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Legionella pneumophila causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against L. pneumophila infection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused by L. pneumophila. Intratracheal (i.t.) administration of L. pneumophila induced the upregulation of both IL-36␣ and IL-36␥ mRNA and protein production in the lung. Compared to the findings for L. pneumophila-infected wildtype (WT) mice, the i.t. administration of L. pneumophila to IL-36 receptor-deficient (IL-36R Ϫ/Ϫ ) mice resulted in increased mortality, a delay in lung bacterial clearance, increased L. pneumophila dissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R Ϫ/Ϫ mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines. Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R Ϫ/Ϫ mice compared to macrophages from WT mice. While L. pneumophila-induced mortality in IL-36␣-or IL-36␥deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36␥ in IL-36␣ Ϫ/Ϫ mice resulted in mortality similar to that observed in IL-36R Ϫ/Ϫ mice, indicating redundant and overlapping roles for these cytokines in experimental murine L. pneumophila pneumonia.

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Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2

Cited by 51 publications

References 60 publications

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

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