Critical Role of Lkb1 in the Maintenance of Alveolar Macrophage Self-Renewal and Immune Homeostasis.

Qianqian Wang,Zhongchao Han,Mingxia Shi,Erlie Jiang,Tengda Li,Song Chen,Xiaoming Feng,Jingru Liu,Huifang Huang,Mingzhe Han,Yuan Meng,Yuan Tao,Jiadi Chen,Qiongmei Yang

doi:10.3389/fimmu.2021.629281

Abstract

Alveolar macrophages (AMs) are pivotal for maintaining lung immune homeostasis. We demonstrated that deletion of liver kinase b1 (Lkb1) in CD11c+ cells led to greatly reduced AM abundance in the lung due to the impaired self-renewal of AMs but not the impeded pre-AM differentiation. Mice with Lkb1-deficient AMs exhibited deteriorated diseases during airway Staphylococcus aureus (S. aureus) infection and allergic inflammation, with excessive accumulation of neutrophils and more severe lung pathology. Drug-mediated AM depletion experiments in wild type mice indicated a cause for AM reduction in aggravated diseases in Lkb1 conditional knockout mice. Transcriptomic sequencing also revealed that Lkb1 inhibited proinflammatory pathways, including IL-17 signaling and neutrophil migration, which might also contribute to the protective function of Lkb1 in AMs. We thus identified Lkb1 as a pivotal regulator that maintains the self-renewal and immune function of AMs.

Highlights

Alveolar macrophages (AMs) act as the first sentinels of the pulmonary innate immune system [1], whose niche in the alveolar space is important for monitoring pulmonary homeostasis
We found that disruption of liver kinase b1 (Lkb1) impaired the self-renewal of AMs, contributing to the reduction of AMs, which led to aggravated symptoms and excessive accumulation of neutrophils in Staphylococcus aureus (S. aureus) pneumonia and asthma
We found that the numbers of AMs and CD103+ dendritic cells (DCs) were prominently decreased in bronchoalveolar lavage (BAL) fluid and/or lungs from Cd11cCreLkb1f/f mice (Figures 1A–D)

Summary

Introduction

Alveolar macrophages (AMs) act as the first sentinels of the pulmonary innate immune system [1], whose niche in the alveolar space is important for monitoring pulmonary homeostasis. AMs are primarily derived from fetal monocytes and maintain their niche by proliferative self-renewal [1, 2]. GM-CSF has a lung-specific role in the perinatal development of AMs via induction of PPAR-g in fetal monocytes, which may promote the differentiation of pre-AMs into mature AMs [4]. Reports have identified that another cytokine, transforming growth factor-b (TGF-b), is critical for the development and maturation of AMs [2, 5]. These studies have examined the development of AMs, the potential molecular mechanisms underlying the self-renewal of terminally differentiated AMs are not well understood

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