Systemic illness triggered by microbial invasion of normally sterile parts of the body is referred to as sepsis. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system, which manifests as excessive inflammation in the presence of immunosuppression. Recent evidence gathered in our laboratory suggests that extracellular adenosine that accumulates during sepsis modulates the immune system by activating adenosine receptors on the surface of immune cells. The production of extracellular adenosine is the consequence of the cellular release of its precursors ATP and ADP, and their sequential cell surface phosphohydrolysis to AMP by ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) and then to adenosine by ecto-5'-nucleotidase (Ecto5'Ntase, CD73). We found that both CD39 and CD73 are upregulated during sepsis and have pivotal roles in restraining inflammation and organ damage by initiating adenosine receptor signaling.
Specific Aim 1 will test the precise mechanisms by which CD39 and CD73 prevent excessive inflammation and organ injury during sepsis using adoptive cell transfer techniques, the "cre-lox" techology, and ex vivo studies on innate immune cells.
Specific Aim 2 will define the molecular basis of the upregulation of CD39 and CD73 on macrophages, which may serve to curb excessive macrophage activation by producing adenosine during sepsis. The overarching goal here is to delineate the role of the ectonucleotidase cascade consisting of CD39 and CD73 in protecting against sepsis and to determine whether this cascade can be therapeutically targeted to manage patients with sepsis.
Sepsis remains the leading cause of morbidity and mortality in critically ill patients. We are studying the function of two ectonucleotidases, CD39 and CD73, which have recently been shown to have beneficial immunomodulatory effects in sepsis. By elucidating how CD39 and CD73 modulate immune and organ function during sepsis, we can utilize this information to develop new pharmacologic approaches targeting CD39 and CD73 to treat patients suffering from sepsis.
|Patel, Nirav; Wu, Wenhui; Mishra, Pankaj K et al. (2014) A2B adenosine receptor induces protective antihelminth type 2 immune responses. Cell Host Microbe 15:339-50|
|Csoka, Balazs; Koscso, Balazs; Toro, Gabor et al. (2014) A2B adenosine receptors prevent insulin resistance by inhibiting adipose tissue inflammation via maintaining alternative macrophage activation. Diabetes 63:850-66|
|Elson, G; Eisenberg, M; Garg, C et al. (2013) Induction of murine adenosine A(2A) receptor expression by LPS: analysis of the 5' upstream promoter. Genes Immun 14:147-53|
|Antonioli, Luca; Pacher, Pal; Vizi, E Sylvester et al. (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19:355-67|
|Ferrante, Christopher James; Pinhal-Enfield, Grace; Elson, Genie et al. (2013) The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4R*) signaling. Inflammation 36:921-31|
|Koscsó, Balázs; Csóka, Balázs; Selmeczy, Zsolt et al. (2012) Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process. J Immunol 188:445-53|
|Haskó, György; Pacher, Pál (2012) Regulation of macrophage function by adenosine. Arterioscler Thromb Vasc Biol 32:865-9|
|Csóka, Balázs; Selmeczy, Zsolt; Koscsó, Balázs et al. (2012) Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J 26:376-86|
|Koscsó, Balázs; Csóka, Balázs; Pacher, Pál et al. (2011) Investigational A? adenosine receptor targeting agents. Expert Opin Investig Drugs 20:757-68|
|Csóka, Balázs; Németh, Zoltán H; Rosenberger, Peter et al. (2010) A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. J Immunol 185:542-50|
Showing the most recent 10 out of 38 publications