Regulation of macrophage alternative activation by eicosanoids
Final Report Abstract
Although the initially proposed hypothesis could not be verified experimentally, we were able to identify novel and clinically relevant effects of PGE2 which underscores the importance of that molecule in macrophage biology and asthma. The macrophage is a key effector cell in innate immunity and in tissue homeostasis, and its functions depend on maturation state. We have shown that PGE2 inhibits macrophage maturation from bone marrow precursors. Although PGE2 is a well known immunomodulator, this previously unrecognized ability to restrain macrophage maturation may have special importance since many disease states, as well as commonly used drugs, like aspirin, modulate PGE2 levels. Another part of my scholarship training involved defining the significance of PGE2 signaling in allergic asthma. PGE2 has been reported to exert complex and sometimes opposing actions in asthma, both promoting and suppressing allergic inflammation in human and animal models. We have shown in a mouse model that PGE2 can attenuate asthma. It does so by inhibiting allergic sensitization, mainly by preventing T-cell polarization. Since exogenous PGE2 could reverse asthma when administered after sensitization occurred, our findings give innovative insights for asthma drug design, perhaps with special interest in population of patients with aspirin exacerbated asthma.
Publications
- Distinct protein kinase A anchoring proteins direct prostaglandin E2 modulation of Toll-like receptor signaling in alveolar macrophages. J Biol Chem. 2011 Mar 18;286(11):8875-83
Kim SH, Serezani CH, Okunishi K, Zaslona Z, Aronoff DM, Peters-Golden M.
- Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling. Blood. 2012 Mar 8;119(10):2358-67
Zaslona Z, Serezani CH, Okunishi K, Aronoff DM, Peters-Golden M.
