Macrophage derived complement factor C3 impacts on cardiac remodeling

Liu, Lulu (2023): Macrophage derived complement factor C3 impacts on cardiac remodeling. Dissertation, LMU München: Medizinische Fakultät

Abstract

Myocardial infarction (MI) is a common condition with strong impact on mortality and morbidity. Coronary occlusion induces myocardial necrosis triggering inflammatory responses of various cell types, leading to myocardial healing or scar formation. The majority of immune cells in the heart are myeloid cells, which play a role in the pathophysiology of MI. They are attracted by inflammatory mediators such as cytokines and chemokines, and recruited to ischemic myocardium. The notion that the complement system mediates immunological defense and is stimulated by MI is supported by prior research. Robust upregulation of the complement system contributes to the postinfarct inflammation process both directly, e.g. by chemoattracting immune cells, and indirectly, such as by inserting the membrane attack complex (MAC) into damaged cells within ischemic myocardium. Complement component 3 (C3) is a key factor in the complement cascade and massive C3 deposition is found in the ischemic region after MI. Blockage or genetic deficiency of C3 has been shown to reduce ischemic injury. However, the underlying mechanisms have been unclear. We utilized C3-tdTomato knock-in reporter mice to monitor C3 expression in immune cells in health and in response to MI, and characterized its role in postinfarct cardiac inflammation and remodeling. Using flow cytometry we identified profound expression of C3 by circulating myeloid cells already in steady state conditions. While presence of C3 was low in healthy mouse hearts, cardiac resident macrophages upregulated C3 within 48h after myocardial ischemia/reperfusion (I/R) injury. Transplantation of donor bone marrow (BM) cells to lethally irradiated mice demonstrated that BM-independent tissue macrophages, which originated from embryonic hematopoiesis, produce this complement factor whereas only minimal amounts of C3 are taken up from blood circulation. In line with this, circulating myeloid cells of bone marrow donors generate C3 in high abundance in recipient mice lacking serum-derived C3. While macrophage C3 had no significant impact on cardiac remodeling after short-term ischemia, tissue resident macrophage derived C3 impacted on infarct size and cardiac remodeling in mice undergoing chronic infarction. Taken together, we provide a comprehensive characterization of C3 expression in immune cells and decipher the upregulation of C3 in cardiac macrophages upon inflammation, shedding light on the importance of intracellularly generated C3 and paving the way for future investigations of post-ischemic inflammation.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: complement C3, myocardial infarction, macrophage, cardiac remodeling
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 26. Juli 2023
• 1. Bericht­erstatter:in: Schulz, Christian