Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis

Németh, Zoltán; Csóka, Balázs; Wilmanski, Jeanette; Xu, Dakang; Lu, Quan; Ledent, Catherine; Deitch, Edwin A.; Pacher, Pál; Spolarics, Zoltán; Haskó, György

doi:10.4049/jimmunol.176.9.5616

Cited by 120 publications

(130 citation statements)

References 76 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…These include HMBG-1, A 2A and C5a. [34][35][36] Our results confirm that MIF is also a promising target for the treatment of sepsis. We also show that MIF/TTX DNA vaccination may provide a new strategy for the prevention and management of sepsis.…”

Section: Mif/ttx Dna Vaccination and Sepsis S Tohyama Et Alsupporting

confidence: 75%

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

et al. 2008

View full text Add to dashboard Cite

Sepsis is a common and frequently fatal condition and there is an urgent need for new therapies that will further reduce sepsis-induced mortality. Macrophage migration inhibitory (MIF) factor is important in the regulation of innate and adaptive immunity and is believed to play a key regulatory role in sepsis and autoimmune disease. As MIF deficiency or immunoneutralization protects mice or rats from fatal endotoxic shock or other inflammatory diseases, we examined whether DNA vaccination against this molecule would also be protective. DNA vaccines can stimulate both humoral and cellular immunity simultaneously and have been shown to be effective against a variety of pathogens or cytokinedriven pathologies. Mice were immunized with a MIF/tetanus toxin (TTX) DNA vaccine and sepsis was then induced by lipopolysaccharide or cecal ligation and puncture. The MIF/ TTX DNA-vaccinated mice were protected from the lethal effect of sepsis compared with control-vaccinated mice in both models. Compared with the control-vaccinated mice, the MIF/TTX DNA-vaccinated mice also showed significantly lower serum tumor necrosis factor (TNF)-a protein levels and reduced mRNA expression of TNF-a, interleukin (IL)-1b, IL-6, macrophage inflammatory protein-2 and Toll-like receptor-4 in the lungs. Thus, the MIF/TTX DNA vaccine may be useful for the prophylaxis of septic shock.

show abstract

Section: Mif/ttx Dna Vaccination and Sepsis S Tohyama Et Alsupporting

confidence: 75%

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

et al. 2008

View full text Add to dashboard Cite

show abstract

“…On the other hand, adenosine receptor ligands that have the ability to facilitate the inflammatory/ immune responses of macrophages represent potential therapies for infectious diseases. A good example for this notion is our recent observation that A 2A receptor blockade can promote antibacterial immunity and bacterial clearance in septic animals (Nemeth et al, 2006). Finally, there is convincing evidence that selective adenosine receptor antagonists (A 2B and A 3 ) are potential therapeutics for asthma and chronic lung disease (Fozard & Hannon, 1999;Fozard & McCarthy, 2002;Blackburn, 2003;Fozard, 2003;Mohsenin & Blackburn, 2006;Spicuzza et al, 2006).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

Self Cite

195

154

View full text Add to dashboard Cite

Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-α, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

show abstract

“…Receptor deletion fails to modify inflammatory markers/injury in some studies [22], reportedly worsens endotoxemic injury in heart [23] and lung [15,24] and improves survival in models of polymicrobial sepsis [25,26]. These divergent outcomes may reflect different cell-and organ-specific effects of A 2A Rs, for example promoting inflammasome formation and macrophage-dependent injury [27], impairing bacterial clearance [25], while activating cardiac survival signalling and suppressing inflammation [3,7,[12][13][14]. Nonetheless, opposing effects of endogenous vs. exogenous (or amplified endogenous) adenosine are evident within cell types, for example inhibiting vs. promoting vascular myocyte NOS activation with inflammation [28].…”

Section: J Ashton and Melissa E Reichelt Denotes Equal First Authormentioning

confidence: 99%

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

Self Cite

View full text Add to dashboard Cite

Influences of adenosine 2A receptor (A 2A R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A 2A R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A 2A R-sensitive genes modified by A 2A R KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of tolllike receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca 2+ signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by A 2A R KO, supporting inflammatory suppression via A 2A R sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A 2A Rs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STATsignalling and cardiac injury without influencing cardiac depression in endotoxemia.

show abstract

Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis

Cited by 120 publications

References 76 publications

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

Shaping of monocyte and macrophage function by adenosine receptors

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Contact Info

Product

Resources

About