Splenic leukocytes define the resolution of inflammation in heart failure

Abstract

Inflammation promotes healing in myocardial infarction but if unresolved, it leads to heart failure. To define the inflammatory and resolving responses, we quantified leukocyte trafficking and specialized proresolving mediators (SPMs) in the infarcted left ventricle and spleen after myocardial infarction, with the goal of distinguishing inflammation from its resolution. Our data suggest that the spleen not only served as a leukocyte reservoir but also was the site where SPMs were actively generated after coronary ligation in mice. Before myocardial infarction, SPMs were more abundant in the spleen than in the left ventricle. At day 1 after coronary ligation, the spleen was depleted of leukocytes, a phenomenon that was associated with greater numbers of leukocytes in the infarcted left ventricle and increased generation of SPMs at the same site, particularly resolvins, maresin, lipoxins, and protectin. In addition, the infarcted left ventricle showed increased expression of genes encoding lipoxygenases and enhanced production of SPMs generated by these enzymes. We found that macrophages were necessary for SPM generation. The abundance of SPMs in the spleen before myocardial infarction and increased SPM concentrations in the infarcted left ventricle within 24 hours after myocardial infarction were temporally correlated with the resolution of inflammation. Thus, the acute inflammatory response coincided with the active resolving phase in post-myocardial infarction and suggests that further investigation into macrophage-derived SPMs in heart failure is warranted.

Obesogenic diet in aging mice disrupts gut microbe composition and alters neutrophi:lymphocyte ratio, leading to inflamed milieu in acute heart failure

“…Diet interaction within the gut defines proximal, distal, and systemic inflammation, which in turn defines interorgan communication. The spleen is a secondary lymphoid organ and serves as a reservoir for the immune cells, regulating host defense or cardiac healing responses specifically in the event of HF (35, 39). The spleen is composed of RP and WP, which are separated by an interface, the MZ.…”

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

“…This suggests that modulating the MI-coordinated miRs could provide hints towards the regulation of post-MI inflammatory responses [62]. Wang et al have reported a cardio-protective role for miR-146a.…”

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

“…From a translational perspective, whether other metabolic disease pathologies alter macrophage function, secretome, and phenotype in aging, needs to be investigated (14,43). In a recent study, Halade et al (44) quantitated leukocyte populations in the splenic reservoir and infarcted LV and further determined the concentrations of specialized proresolving mediators that limit cardiac inflammation post-MI. This study clearly suggests that leukocytes mobilize from the spleen to the infarcted heart to produce resolvins, lipoxins, maresins, and protectins in the infarcted heart during the acute inflammatory response, suggesting that acute inflammatory response coincides with resolving response in cardiac healing.…”

“…What is first in cardiac healing and repair after ischemic injury? Is it inflammation, or is it a resolution of inflammation, or do both overlap in a time-dependent manner to set the stage for healing program of myocardium after MI (44)? In response to injury, infection, or stress, an acute inflammatory response primarily involves early tissue edema within seconds to minutes followed by infiltration of neutrophils within minutes to hours and later mononuclear cells, some of which transition at maturity to macrophages.…”

“…In response to injury, infection, or stress, an acute inflammatory response primarily involves early tissue edema within seconds to minutes followed by infiltration of neutrophils within minutes to hours and later mononuclear cells, some of which transition at maturity to macrophages. During host-mediated acute inflammation that resolves and returns the infarcted cardiac tissue to homeostasis by formation of SPMs, such as lipoxins, Rvs, protectins, and MaRs (44). The main hallmark of chronic inflammation (particularly in aging marked with decreased biosynthesis of SPMs) is when acute inflammation fails to resolve, or excessive inflammation leads to bystander tissue injury.…”