GATA3 Macrophages as a Contributing Cause of Cardiac Fibrosis
The innate immune cells called macrophages are deeply involved in both inflammation and regeneration. They adopt different phenotypes, or polarizations, depending on circumstances, such as the M1 polarization (inflammatory, aggressive in pursuit of pathogens) and M2 polarization (pro-regenerative, anti-inflammatory). The simple view of macrophage polarization in aging tissues is that problems arise with an excess of M1 macrophages, and this is a part of the chronic inflammation that is characteristic of aging. It is well known that inflammation, when maintained over the long term, is highly disruptive of tissue function, and contributes to the progression of all of the common age-related disease.
The open access commentary here makes the point that this model of polarization and inflammation is overly simplistic, and the reality is much more complex. The researchers illustrate this with data on M2 macrophages expressing GATA3, suggesting that it is these cells, rather than pro-inflammatory M1 macrophages, that are contributing to the fibrosis that appears in cardiac tissue with age. Fibrosis is a disarray of tissue maintenance and regeneration, involving the deposition of scar-like collagen structures that degrade tissue function. The usual view of fibrosis is that it is a consequence of inflammation, very connected to the inflammatory presence of senescent cells, for example. Given that, it is quite interesting to see this sort of contradictory data.
Chronic inflammation is believed to contribute to the pathogenesis of many age-related diseases including cardiovascular disease. Chronic inflammation, particularly from activation of innate immunity, is highly sensitive to changes in the tissue environment that is associated with aging. The immune cell type that is particularly influenced by changes in its microenvironment is the monocyte/macrophage. These cells display a high level of plasticity and heterogeneity in response to their environmental cues. For example, based on the response of cultured macrophages to treatment with IL-4 or interferon γ, cells have been proposed to polarize to either M2 or M1 phenotypes, respectively. Although the M1-M2 polarization concept is useful in describing the two extremes of macrophage phenotypes, the concept does not accurately recapitulate the complex response of cells to their driving tissue microenvironment in vivo.
The plasticity of monocytes/macrophages are determined by the constellation of transcription factors that are activated and expressed in response to environmental cues. To understand the role of GATA3 transcription factor in the pathogenesis of cardiac diseases, we generated myeloid-specific GATA3 knockout mice and found that their cardiac function is significantly improved in response to ischemia or pressure overload compared with the GATA3 sufficient control group. Analysis of the profile of monocytes/macrophages in vivo revealed that GATA3-positive macrophages are not found in the healthy adult tissue. In the setting of a myocardial infarction, however, the deficiency of GATA3-positive macrophages led to a significant improvement of cardiac function compared with the GATA3 sufficient control group.
This improvement was found to be associated with the presence of many pro-inflammatory macrophages, but, few "anti-inflammatory/reparative" macrophages. This was unexpected because the prevailing hypothesis is that controlling the pro-inflammatory pathways may improve cardiac function. Our data suggest that exuberant repair, rather than unrestrained inflammation, may contribute to the excessive and maladaptive remodeling of the myocardium in the post myocardial infarction setting. Extensive evidence suggests that the aging heart undergoes fibrotic remodeling. Although targeting of pro-inflammatory pathways is thought to be an important strategy to control excessive tissue fibrosis, numerous anti-inflammatory drugs have been found to have little or no therapeutic benefit in fibrotic diseases. Our data suggest that GATA3-positive macrophages, which presumably display an M2 phenotype, are highly fibrogenic. It is therefore possible that targeting a subset of inflammatory cells, rather than global inflammation, may be a useful therapeutic strategy to control fibrotic diseases associated with aging.