Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis

Yi Yao,James Glassbrook,Queping Liu,Xiaojun Wu,Frederic Geissmann,Zheng Dong,Namir Khalasawi,Congcong Yin,Qijun Yi,Li Zhou,Indra Adrianto,Qing-Sheng Mi

doi:10.1038/s41467-020-17630-6

Abstract

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.

Highlights

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions
histone deacetylase 3 (HDAC3) was expressed in lung fetal macrophages at E14.5 and in preAMs at E16.5 and E18.5, but its expression was dramatically increased in AMs from the young (P14, ~20-fold) and adult (~40-fold) mice. These results suggest that HDAC3 is potentially involved in AM embryonic development and maintenance after birth
We found that the frequency and number of AMs were dramatically reduced in CD11cCreHdac3fl/flcKO mice compared to their wild type (WT) counterparts (Fig. 2d), and that CD11b was highly expressed on AMs from CD11cCreHdac3fl/flcKO mice (Fig. 2e)

Summary

Introduction

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. We show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Transforming growth factor-β (TGF-β) is crucial for the embryonic differentiation of fetal monocytes into preAMs, their postnatal maturation, as well as the homeostasis of adult AMs11. Both GM-CSF and TGFβ signaling pathways induce the expression of PPAR-γ, a signature transcription factor essential for the development of AMs7,11. HDACs exhibit limited substrate specificity and rely on transcription factors with specific

Objectives

Methods

Results

Conclusion