Abstract
Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.
Highlights
Macrophages are widely distributed through vertebrate tissues and play essential roles in homeostasis, and in response to injury
Reports suggest targeting the enzymatic core of polycomb II, enhancer of zeste homolog 2 (EZH2), impacts immune responses in the nonmalignant state.[15]
It is timely to investigate the role of EZH2 in inflammation, and immunity
Summary
Macrophages are widely distributed through vertebrate tissues and play essential roles in homeostasis, and in response to injury. Pro-inflammatory outcomes were documented following suppression of EZH2 in inflammatory bowel disease models11-1 3 and Kras-driven lung cancer inflammation.[14] In contrast, Zhang et al demonstrated that EZH2 in the macrophage drives experimental autoimmune diseases including experimental autoimmune encephalomyelitis and colitis. In this latter study, loss of EZH2 reduced inflammatory responses to stimulus and so reduced disease severity, pointing the way to pharmacological inhibition of EZH2 as a therapeutic strategy in multiple sclerosis.[15] These discrepancies may result from differential impacts on different cell types, and gene expression programs involved in immune response elaboration, and require further analysis. The complex actions of EZH2 on innate immune responses are important to consider with the availability of drugs targeting this epigenetic regulator in patients for cancer indications, and suggestions of a role in managing autoimmune disease such as multiple sclerosis
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