Scientists at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center report that the location of immune cells in the body determines whether they help or harm the development of heart disease. They say their study (“Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy”), which appears in PNAS, supports the idea that the immune system directly impacts heart failure.
The team’s research demonstrated that immune cells located within the heart are activated quickly after injury and protect the heart from damage. However, at later stages of injury, immune cells circulating in the blood enter the heart and worsen disease. Blocking migration of these late stage blood-borne immune cells to the heart improved symptoms in mouse models of heart disease. Despite the cells being the same type--macrophages that engulf cellular debris--the two populations have different functions.
“Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities,” write the investigators.
“Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.”
"We showed immune cells in the heart act as 'good guys' and reduce heart damage, while immune cells that are in the bloodstream and later migrate to the heart act as 'bad guys' and promote damage," said lead author Xudong Liao PhD, assistant professor of medicine at Case Western Reserve University School of Medicine.
Non-ischemic cardiomyopathy decreases the heart's ability to pump blood, and can be inherited, or a side effect of hypertension or other heart valve conditions. Dr. Liao and colleagues showed high pressure in the heart affected by the disease causes beneficial immune cells in the heart to reproduce. Pressure increases activate genetic factors that promote local, beneficial immune cell growth. But as other immune cells begin to arrive, conditions worsen. The researchers showed newly arrived immune cells prevent local immune cells from helping the heart adapt to damage.
The discovery led the researchers to investigate ways to preserve the beneficial effects of immune cells found inside the heart. The team injected mouse bloodstreams with flagged immune cells and tracked how the cells migrated to the heart. They then injected the mice with a small inhibitor molecule that prevents the cells from migrating.
"Strikingly, if you block the immune cells in the bloodstream from entering the heart, you can ameliorate heart failure in our animal models" said senior author Mukesh K. Jain, M.D., vice dean for medical sciences at Case Western Reserve University School of Medicine and chief scientific officer at University Hospitals Cleveland Medical Center. Blocking immune cell migration represents a novel therapeutic approach for non-ischemic cardiomyopathy. According to Dr. Jain, a patent has already been filed in relation to the discovery.