The transcription factor basic helix loop helix, member e40 is required for establishment of proper peritoneal macrophage identity

Abstract

Tissue-resident macrophages occupy key roles in immunity and physiology, both as sensors of and first responders to homeostatic perturbations. The majority of resident macrophages derive from embryonic progenitors and self-maintain locally as unique tissue-specific populations. The transcriptional basis for tissue-resident macrophage identity is poorly understood. We have observed that the transcription factor basic helix loop helix, member e40 (Bhlhe40) is highly expressed in a subset of hematopoietic cell types, including peritoneal macrophages. Based on these data, we hypothesized that Bhlhe40 is a key part of the peritoneal macrophage transcriptional network and adapts nascent macrophages to the functional demands of the peritoneal niche. We have found that peritoneal macrophages are selectively reduced in Bhlhe40^−/− mice, in contrast to other resident macrophages. Furthermore, in the absence of Bhlhe40 the remaining large peritoneal macrophages (LPMs) are replaced by monocyte-derived cells to a greater extent than in wildtype mice. Bhlhe40-deficient peritoneal macrophages exhibit altered polarization and self-renewal. Mixed bone marrow chimeras and other approaches demonstrated a specific, intrinsic defect in mature Bhlhe40^−/− LPMs. Using models of peritoneal immunity, we observed impaired responses of Bhlhe40-deficient peritoneal macrophages. Our preliminary findings demonstrate a role for Bhlhe40 in peritoneal macrophage biology and lead us to propose that Bhlhe40 transcriptionally controls a tissue-specific program in macrophages tailored to the peritoneal environment.