Abstract 3344: Tumor Necrosis Factor Signaling in Macrophages Modulates Juxtacrine Macrophage-Myocyte Interactions in Heart Failure
We have previously shown that macrophage-myocyte physical interactions in heart failure (HF) are sufficient to induce myocyte dysfunction and reactive oxygen species (ROS) generation; however, the role of tumor necrosis factor-α (TNF) receptor (R) signaling in these effects is unknown. Prior studies have shown that TNFR1 exacerbates, whereas TNFR2 ameliorates, remodeling and macrophage infiltration in HF. Hence, we hypothesized that macrophage localized TNFR1/R2 would impart analogous divergent effects on macrophage-mediated myocyte dysfunction. Thioglycollate-elicited peritoneal macrophages from wild-type (WT) (n=4), TNFR1−/− (n=4), and TNFR2−/− (n=5) mice with coronary ligation-induced HF were co-cultured with adult WT myocytes, and myocyte contraction was assessed in the presence or absence of myocyte-macrophage physical contact after 15 minutes. In the absence of physical contact, sarcomere shortening (1 Hz) was 11.9±0.4%, and shortening was significantly (p<0.05) depressed upon physical contact with macrophages derived from WT, TNFR1−/−, and TNFR2−/− HF mice. However, shortening was significantly (p<0.05) more depressed upon myocyte physical association with TNFR2−/− HF-derived macrophages (WT 5.0±1.5%, TNFR1−/− 5.3±1.6%, TNFR2−/− 2.8±0.2%). In parallel studies, cardiomyocytes were loaded with the fluorescent indicator DCF-DA to monitor ROS generation after macrophage attachment. Myocyte attachment to WT HF and TNFR2−/− HF macrophages induced a 4-fold increase in myocyte ROS over baseline. However, ROS augmentation was markedly diminished (p<0.05) with attachment of TNFR1−/− HF macrophages.
Conclusion: physical association with HF-derived activated macrophages is sufficient to induce both contractile dysfunction and ROS in myocytes. Macrophage TNFR2 signaling attenuates ROS generation and TNFR1-dependent macrophage-induced contractile dysfunction in myocytes. Although macrophage contact induces both myocyte ROS and contractile depression, oxygen free radicals are not required for the production of contractile dysfunction. Analogous macrophage-myocyte interactions in the failing heart may contribute to the divergent effects of TNFR1 and TNFR2 on myocardial inflammatory activation and remodeling.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).