E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae

Aronoff, David M.; Bergin, Ingrid L.; Lewis, Casey; Goel, Deepti; O’Brien, Edmund; Peters‐Golden, Marc; Mancuso, Peter

doi:10.1016/j.prostaglandins.2012.03.002

Cited by 23 publications

(35 citation statements)

References 64 publications

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“…PGE 2 also inhibits B cell proliferation and Ig production; enhances production of immunosuppressive cytokines IL-10 and IL-6; inhibits leukocyte chemotaxis and leukotriene synthesis; and inhibits phagocytosis of bacteria in macrophages (22,23,53). We speculate that these mechanisms play a key role in PGE 2 -induced immunosuppression in response to S. mucilaginosus.…”

Section: Discussionmentioning

confidence: 83%

“…COX-2-deficient mice display resistance against detrimental effects of endotoxemia (50,51). Modulation of immune response by COX-2 is largely related to an increased production of PGE 2 , which has been shown to be immunosuppressive in animal models of bacterial pneumonias and sepsis (21,23,(52)(53)(54). PGE 2 can also be produced by induction of mPGE synthases, depending on the stimulus (55,56).…”

Section: Discussionmentioning

confidence: 99%

“…Engagement of TLRs leads to activation of signaling pathways that results in generation of cytokines, chemokines, and lipid mediators produced by cyclooxygenases that are critical for host immune response (19,20). We and others have shown that activation of cyclooxygenase-2 (COX-2) and production of lipid mediators play a pivotal immunomodulatory role in fungal, viral, and bacterial infections (21)(22)(23)(24)(25). In particular, PGE 2 has immunosuppressive effects and impairs bacterial clearance (22,23,(26)(27)(28)(29), whereas PGD 2 has been shown to have immunostimulatory effects (30,31).…”

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confidence: 99%

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Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

Yuan

Panchal

Syed

et al. 2013

The Journal of Immunology

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Stomatococcus mucilaginosus is an oral commensal that has been occasionally reported to cause severe infections in immunocompromised patients. There is no information about the pathogenic role of S. mucilaginosus in airway infections. In a cohort of 182 subjects with bronchiectasis, we found that 9% were colonized with S. mucilaginosus in their lower airways by culture growth from bronchoalveolar lavage. To address the pathogenic potential of S.mucilaginosus, we developed a murine model of S. mucilaginosus lung infection. Intratracheal injection of S. mucilaginosus in C57BL/6 mice resulted in a neutrophilic influx with production of proinflammatory cytokines, chemokines, and lipid mediators, mainly PGE2 with induction of cyclooxygenase-2 (COX-2) in the lungs. Presence of TLR2 was necessary for induction of COX-2 and production of PGE2 by S. mucilaginosus. TLR2-deficient mice showed an enhanced clearance of S. mucilaginosus compared with wild-type mice. Administration of PGE2 to TLR2−/− mice resulted in impaired clearance of S. mucilaginosus, suggesting a key role for COX-2–induced PGE2 production in immune response to S. mucilaginosus. Mechanistically, induction of COX-2 in macrophages was dependent on the p38-ERK/MAPK signaling pathway. Furthermore, mice treated with S. mucilaginosus and Pseudomonas aeruginosa showed an increased mortality compared with mice treated with PA103 or S. mucilaginosus alone. Inhibition of COX-2 significantly improved survival in mice infected with PA103 and S. mucilaginosus. These data provide novel insights into the bacteriology and personalized microbiome in patients with bronchiectasis and suggest a pathogenic role for S. mucilaginosus in patients with bronchiectasis.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

Yuan

Panchal

Syed

et al. 2013

The Journal of Immunology

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“…Inhibiting PGE 2 production during Streptococcus infection enhances macrophage phagocytosis and generation of reactive oxygen species, aiding in bacterial clearance (Stables et al, 2010). PGE 2 signaling post- Streptococcus infection relies on both EP2 and EP4 signaling (Aronoff et al, 2012; Szymanski et al, 2012). EP2 −/− murine alveolar macrophages demonstrate enhanced phagocytosis, intracellular killing, and increased generation of reactive oxygen in vitro , while EP2 −/− mice demonstrate improved bacterial clearance and survival post-infection with S. pneumoniae .…”

Section: The Role Of Pge2 During Bacterial Infectionmentioning

confidence: 99%

“…Activation of mammalian neutrophils by formylmethionyl-leucyl-phenylalanine (fMLP) is inhibited by PGE 2 in an EP2-dependent manner (Takenawa et al, 1986; Burelout et al, 2004, 2007). Inhibition of EP2 signaling improves neutrophil migration to promote bacterial clearing and enhances mouse survival following intratracheal infection with Pseudomonas aeruginosa (Sadikot et al, 2007; Aronoff et al, 2012). Bacterial pathogens and their structural components directly promote PGE 2 synthesis by neutrophils during infections.…”

Section: Introductionmentioning

confidence: 99%

PGE2 suppression of innate immunity during mucosal bacterial infection

Agard¹,

Asakrah²,

Morici³

2013

Front. Cell. Infect. Microbiol.

125

116

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Prostaglandin E2 (PGE2) is an important lipid mediator in inflammatory and immune responses during acute and chronic infections. Upon stimulation by various proinflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, PGE2 synthesis is upregulated by the expression of cyclooxygenases. Biologically active PGE2 is then able to signal through four primary receptors to elicit a response. PGE2 is a critical molecule that regulates the activation, maturation, migration, and cytokine secretion of several immune cells, particularly those involved in innate immunity such as macrophages, neutrophils, natural killer cells, and dendritic cells. Both Gram-negative and Gram-positive bacteria can induce PGE2 synthesis to regulate immune responses during bacterial pathogenesis. This review will focus on PGE2 in innate immunity and how bacterial pathogens influence PGE2 production during enteric and pulmonary infections. The conserved ability of many bacterial pathogens to promote PGE2 responses during infection suggests a common signaling mechanism to deter protective pro-inflammatory immune responses. Inhibition of PGE2 production and signaling during infection may represent a therapeutic alternative to treat bacterial infections. Further study of the immunosuppressive effects of PGE2 on innate immunity will lead to a better understanding of potential therapeutic targets within the PGE2 pathway.

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Pathways mediating resolution of inflammation: when enough is too much

2013

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Patients with critical illness, and in particular sepsis, are now recognized to undergo unifying, pathogenic disturbances of immune function. Whilst scientific and therapeutic focus has traditionally been on understanding and modulating the initial pro-inflammatory limb, recent years have witnessed a refocusing on the development and importance of immunosuppressive 'anti-inflammatory' pathways. Several mechanisms are known to drive this phenomenon; however, no overriding conceptual framework justifies them. In this article we review the contribution of pro-resolution pathways to this phenotype, describing the observed immune alterations in terms of either a failure of resolution of inflammation or the persistence of pro-resolution processes causing inappropriate 'injurious resolution'-a novel hypothesis. The dysregulation of key processes in critical illness, including apoptosis of infiltrating neutrophils and their efferocytosis by macrophages, are discussed, along with the emerging role of specialized cell subtypes Gr1(+) CD11b(+) myeloid-derived suppressor cells and CD4(+) CD25(+) FoxP3(+) T-regulatory cells.

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E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae

Cited by 23 publications

References 64 publications

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

PGE2 suppression of innate immunity during mucosal bacterial infection

Pathways mediating resolution of inflammation: when enough is too much

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