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The innate immune cells called macrophages are vitally important to the health and function of tissues. They help to coordinate the intricate dance of stem cells, somatic cells, and immune cells that produces tissue regrowth and tissue maintenance. They destroy errant cells and pathogens. They have a variety of other roles as well. But where do macrophages come from? While some macrophages are generated within tissues, it is generally the case that in damaged or diseased tissues, most macrophages were originally monocytes. Circulating monocytes in the bloodstream enter tissues in response to chemical cues and then transform into macrophages that set to work to try to aid in repair and regeneration. Monocytes themselves are generated by cell populations in the bone marrow that descend from hematopoietic stem cells. At any given time about half of the monocytes in the body reside in the spleen, acting as a reserve that can leap into action when required.
Thus in any given situation of injury or disease in which the presence of macrophages would be beneficial, any process that prevents monocytes from arriving and transforming into macrophages will make things worse. Interestingly, it isn’t always the case that more macrophages will improve the situation. Atherosclerosis, for example, is a condition in which fatty lesions that narrow and weaken blood vessels form because the macrophages responsible for repairing the problem become overwhelmed by cholesterol and die, adding their debris to the lesion. Adding more macrophages accelerates the process, which is why animal models of atherosclerosis often use angiotensin II to cause monocytes to leave the spleen and enter the bloodstream, to make lesions form faster.
In today’s open access research materials, the authors report on a mechanism operating in heart tissue that impairs the ability of monocytes to become macrophages of a type and behavior suitable for tissue regeneration. Blocking this mechanism improves tissue maintenance, heart structure, and heart function. It is a recent example of many research results published over the past few years that, collectively, demonstrate the great importance of macrophage dynamics to normal tissue function. Macrophages have several phenotypes or polarizations, states distinguished by different markers and behaviors. The ones of interest are M1, inflammatory and aggressive, versus M2, anti-inflammatory and regenerative. A lot of issues in aging are marked by the presence of too many M1 macrophages, and there is considerable interest in the research community regarding the development of means to alter this balance.
A new study provides evidence that when circulating anti-inflammatory white blood cells known as monocytes fail to properly differentiate into macrophages – the cells that engulf and digest cellular debris, bacteria and viruses – certain forms of heart disease may result. The research shows the presence of a specific protein prevents this monocyte-to-macrophage transition from occurring in the heart. This triggers a cascade of events that can cause heart muscle inflammation, or myocarditis; remodeling of the cardiac muscle structure; enlargement of the heart, or dilated cardiomyopathy; and weakening of the organ’s ability to pump blood. Eventually, this can result in heart failure.
In previous live mouse and “test-tube” laboratory studies, researchers determined that IL-17A stimulates spindle-shaped cardiac cells called fibroblasts to release a mediator that causes one type of monocyte, an inflammatory cell known as Ly6Chi to accumulate in greater numbers in the heart than the anti-inflammatory type known as Ly6Clo.
“The good news, also shown by our study, is that blocking a key protein, known as interleukin-17A or IL-17A, permits the differentiation of anti-inflammatory monocytes, promotes healthy cardiac function, and allows the newly created macrophages to protect, rather than attack, cardiac muscle. We knew that cardiac fibroblasts stimulated by IL-17A are potent producers of a protein, granulocyte-macrophage colony-stimulating factor, or GM-CSF, that is a cytokine, a molecule that evokes an immune response and inflammation in tissues. So, thinking that GM-CSF might be the key to why differentiation is disrupted, we added antibodies against GM-CSF to a mix of cardiac fibroblasts, IL-17A, and Ly6Clo and found that we could counter IL-17A’s influence on the fibroblasts, and in turn, restore normal Ly6Clo monocyte-to-macrophage differentiation,”
Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation.
We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.