Inflammatory Resolution: The Role of Cyclopentenone Prostaglandins, Adenosine and Lymphocyte Trafficking.

Abstract

Inflammation is fundamentally a beneficial response leading to removal of the offending factor, and resolution, an active regulated process that is essential to maintain tissue integrity and function. Previous work in our department showed a role for COX-2 derived PGD2 and its cyclopentenone metabolite 15d-PGJ2 during resolution in a pleurisy model. I investigated mice lacking hPGD2S and therefore absent PGD2 and 15d-PGJ2 by inducing peritonitis with zymosan. The resolution of peritonitis in hPGD2S mice was delayed compared to wild type C57black VI mice. PGD2 via its action on the DP1 receptor controls the balance of pro- versus antiinflammatory cytokines that regulate leukocyte influx as well as monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Previous data that laid doubt to the presence of 15d-PGJ2 in in vivo models and questioned its role in resolution of innate inflammation. By measurement of peritoneal exudates with LC-MSMS, there is definitive proof that 15d-PGJ2 is synthesised during mammalian inflammatory responses. When the cellular profile was examined by flow cytometry, a biphasic response of lymphocytes was observed with the disappearance during acute inflammation with activation of the DP-1 receptor. The profile of lymphocytes that reappear during resolution differed from the naïve state and comprised of B1, NK, gamma/delta T, CD4+/CD25+ and B2 cells. The lymphocytes do not appear to have a role in resolution as lymphocyte deficient RAG2-/- and wild types resolve uniformly. However repopulating lymphocytes are critical for modulating responses to superinfection as observed by the exaggerated peritonitis/death of RAG2-/- mice when exposed to group B streptococcus following zymosan. In gp91phox-/- mice, an experimental model of CGD, where the peritonitis failed to resolve, the adaptive transfer of resolution phase lymphocytes into the peritoneum, was protective against superinfection. Furthermore in wild type mice when the anti-inflammatory adenosine and downstream cAMP were measured in peritonitis, there was a biphasic response. In gp91phox-/- mice, both adenosine and cAMP were significantly lower at onset and again at resolution. Adenosine, signalling 15 through its A2A receptor and therefore elevating cAMP is not only anti-inflammatory, but also importantly, it does not impair pro-resolution pathways as antagonism of the A2A receptor worsens acute inflammation and prolongs resolution. In summary, resolution is an active regulated process that requires the input COX-2 derived PGD2 as well as anti-inflammatory A2A receptor activation. To further refine this model it was shown that repopulating lymphocytes are essential to prevent super-infection and persistence of inflammation.