Abstract Mucosal immunity is critical to survival, with huge attention at present due to the Coronovirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 closest to application due to the availability of highly-specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage, with some conflicting reports. Here we show EZH2 acts in macrophages to limit inflammatory responses to activation, and selective genetic deletion results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, EZH2 is required for neutrophil chemotaxis, and animals lacking neutrophil EZH2 show increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid cells, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity, however, may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome (ARDS). Digest Epigenetic control of mucosal immunity is important, and has translational relevance with the advent of inhibitor drugs now in the clinic for cancer indications. Here we show divergent role for EZH2 in macrophages and neutrophils. Loss of EZH2 in macrophages results in a gain of inflammatory and immune function, and protection from pneumonia. However, EZH2 is required for neutrophil chemotaxis, resulting in impaired anti-bacterial defence. We show that inhibition, or loss of EZH2 in macrophages results in a gain of immune function, with increased responses to infectious mimics such as LPS. However, the impact was far more dramatic in-vivo, with striking protection from the consequences of infection with pneumococcal bacteria. Loss of EZH2 resulted in a gain in activity of a number of inflammatory signaling cascades, including NFkB, PPARg, and IRFs1, and 7. This widespread macrophage re-programming varied between macrophages sites of origin, with the greatest impact seen in peritoneal macrophages which resulted in emergence of a new population of MerTK low cells. In contrast, in the neutrophils loss of EZH2 greatly impairs motility, and chemotaxis. This results in dramatic impairment of immune responses to the same pneumococcal infection. Extension of these studies to the mucosal epithelium revealed that EZH2 in bronchoalveolar epithelial cells had no impact on responses to infection with influenza. Taken together EZH2 plays diverse roles in the myeloid lineage, with profound impacts on inflammatory responses. The most striking observation was the difference seen between macrophages and neutrophils. EZH2 inhibition is likely to greatly impair mucosal immunity. Impact Statement Here we show a striking, but highly cell-type specific impact of the EZH2 methyltransferase on inflammatory, and anti-infective circuits; inhibition of EZH2 in macrophages augments macrophage cytokine production, but by impairing neutrophil migration impairs anti-bacterial responses.

Ezh2 restrains macrophage inflammatory responses, and is critical for neutrophil migration in response to pulmonary infection