Chronic inflammation is a major component of degenerative aging. Short-term inflammatory signaling is necessary for the immune system to function, including its role in tissue regeneration following injury, as well as defense against malfunctioning, potentially cancerous cells. But when sustained over the long term without resolution, that same signaling becomes disruptive to tissue structure and function. It hinders regeneration, it encourages fibrosis and cancerous growth, and leads to an immune system less able to defend against pathogens.
The primary approach towards the development of novel means of suppressing unwanted inflammation is to interfere in specific inflammatory signals or the regulatory mechanisms that generate those signals. The challenge lies in the fact that the same signals and mechanisms are involved in both necessary short-term inflammation and undesirable long-term inflammation. Thus existing approaches produce an unwanted suppression of desirable features of the immune system, side-effects that harm long-term health.
Thus some researchers are attempting to identify aspects of the inflamed immune system that are (a) more relevant to chronic inflammation and less relevant to short-term inflammation, and (b) can be targeted in isolation of the rest of the immune system. In principle there should be ways to reduce undesirable effects while still obtaining benefit in adjusting the way in which the inflamed immune system operates. Today's open access paper reports on one such approach, a step in the right direction in that the researchers identify a way to suppress the contribution of monocyte cells to chronic inflammation without impairing the immediate inflammatory response.
Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans
The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins.
In this study we characterised the epoxy-oxylipin biosynthetic machinery in humans under baseline and inflammatory conditions demonstrating that blocking soluble epoxide hydrolase (sEH) significantly elevated the epoxy-oxylipins 12,13-EpOME and 14,15-EET. With little effect on the salient features of inflammation, except for accelerated pain resolution, sEH inhibition most notably reduced numbers of intermediate monocytes in blood and in inflamed tissue via the inhibition of p38 MAPK by 12,13-EpOME.
Reduced intermediate monocytes during tissue resolution uncovered potential a role for these cells in maintaining CD4 T cell viability and phenotype on the one hand, but also revealed their ability to drive cells death via cytotoxic CD8 T cells on the other. With clinical studies demonstrating that sEH inhibition is safe and well tolerated, therefore, sEH inhibition presents a hitherto unappreciated way of reducing inflammatory intermediate monocytes, which are implicated in the pathogenesis of chronic inflammatory disease.
View the full article at FightAging
