Abstract
Targeting airway goblet cell metaplasia is a novel strategy that can potentially reduce the chronic obstructive pulmonary disease (COPD) symptoms. Tumor suppressor liver kinase B1 (LKB1) is an important regulator of the proliferation and differentiation of stem/progenitor cells. In this study, we report that LKB1 expression was downregulated in the lungs of patients with COPD and in those of cigarette smoke-exposed mice. Nkx2.1Cre; Lkb1f/f mice with conditional loss of Lkb1 in mouse lung epithelium displayed airway mucus hypersecretion and pulmonary macrophage infiltration. Single-cell transcriptomic analysis of the lung tissues from Nkx2.1Cre; Lkb1f/f mice further revealed that airway goblet cell differentiation was altered in the absence of LKB1. An organoid culture study demonstrated that Lkb1 deficiency in mouse airway (club) progenitor cells promoted the expression of FIZZ1/RELM-α, which drove airway goblet cell differentiation and pulmonary macrophage recruitment. Additionally, monocyte-derived macrophages in the lungs of Nkx2.1Cre; Lkb1f/f mice exhibited an alternatively activated M2 phenotype, while expressing RELM-α, which subsequently aggravated airway goblet cell metaplasia. Our findings suggest that the LKB1-mediated crosstalk between airway progenitor cells and macrophages regulates airway goblet cell metaplasia. Moreover, our data suggest that LKB1 agonists might serve as a potential therapeutic option to treat respiratory disorders associated with goblet cell metaplasia.
Highlights
Airway mucus is an important part of the fundamental host defense system that enables the clearing of inhaled particles by trapping pathogens to preserve airway sterility and homeostasis
We found that compared with normal healthy controls, the liver kinase B1 (LKB1) transcript level remained unchanged in the airway epithelial cells from patients with cystic fibrosis (Figure S2)
When LKB1 expression is inhibited from the embryonic stage, goblet cell metaplasia develops in the adult stage
Summary
Airway mucus is an important part of the fundamental host defense system that enables the clearing of inhaled particles by trapping pathogens to preserve airway sterility and homeostasis. Goblet cell metaplasia-associated excessive airway mucus is one of the most common symptoms of several lung diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD), leading to severe clinical outcomes in patients [1,2,3]. Foxp1/4 restricts goblet cell differentiation during lung development and regeneration by regulating the anterior gradient 2 (Agr2) [4]. The club cell-specific activation of β-catenin at the later stages of lung development leads to goblet cell metaplasia, which is associated with an increased secretion of mucins [13]. The epithelial-specific deletion of receptor-like tyrosine kinase (Ryk) gradually increases the number of goblet cells during lung development, while the club cell-specific deletion of Ryk in adult stages drives goblet cell metaplasia and mucus hypersecretion during regeneration [5]. The regulation of goblet cell differentiation by inflammatory cells remains largely unexplored
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