Mechanisms of Cardiac Injury Resolution by CX3CR1+ Macrophages

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Heart failure (HF) due to ischemic heart diseases such as myocardial infarction (MI) remains a global health crisis and new therapies to limit the progression to HF after MI are greatly needed. Patient outcomes after MI largely depend on the magnitude, severity, and duration of tissue remodeling - a complex process that involves acute and chronic changes in the structure, function, and cellular makeup of the heart in response to injury. In particular, proper scar formation is required for adequate healing and maintenance of cardiac function. However, the injured heart is predisposed to chronic inflammation and excess scarring, or fibrosis, which promotes cardiac dysfunction, pathological remodeling, and propensity towards HF. It is well recognized that the inflammatory response during post-MI remodeling is a critical determinant of whether scar formation proceeds in a beneficial way to achieve tissue healing or progresses to chronic pathological fibrosis. Inflammation in the post-MI setting is both beneficial and detrimental. For example, acute MI patients given broad-acting anti-inflammatory agents are predisposed to wall rupture due to a muted fibrotic response, highlighting the critical role of inflammatory cells in mediating acute healing through fibroblast activity. Prior work from the proposal PI as a postdoctoral fellow uncovered an unexpected paradigm where activating a subset of innate immune cells, cardiac tissue- resident macrophages (TRMs) expressing the chemokine receptor CX3CR1 (CX3), improved cardiac wound healing and limited fibrosis after MI in a mouse model. This provided proof-of-concept evidence that certain aspects of the inflammatory response can be selectively enhanced to keep post-MI remodeling in balance and improve outcomes. However, the precise cellular signals that drive this pro-healing phenotype in macrophages remain unclear, preventing the development of therapies that harness these beneficial effects of cardiac TRMs. This proposal seeks to address this by elucidating the cellular and molecular mechanisms whereby CX3+ TRMs resolve chronic inflammation and pathological fibrosis in a mouse MI model. To achieve this, we will employ two distinct genetic mouse models to inhibit CX3+ TRMs, genetic macrophage tracking, a well-defined surgical model of MI, and cutting-edge multi-omics, biophysical, and molecular assays of cardiac fibrosis. In Specific Aim 1, we will test the hypothesis that CX3 is required for cardiac TRMs to promote healing post-MI, through attenuating fibroblast expansion and extracellular matrix remodeling. In Specific Aim 2, we leverage a comprehensive spatial transcriptomics and proteomics approach to test the hypothesis that local cardiac microenvironment cues from other subsets of inflammatory macrophages prevent resolution of fibrosis and tissue healing by CX3+ TRMs. Overall our Proposal will determine how CX3+ TRMs act mechanistically to promote myocardial healing and resolve chronic inflammation and fibrosis. These data will reveal potential therapeutic pathways to enhance infarct repair by promoting CX3+ TRM functions. Our long-term goal is to contribute novel insights to better understand and therapeutically modulate cardiac tissue remodeling, thus limiting the progression of HF.