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LKB1 deficiency upregulates RELM-α to drive airway goblet cell metaplasia.
- Source :
-
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Dec 18; Vol. 79 (1), pp. 42. Date of Electronic Publication: 2021 Dec 18. - Publication Year :
- 2021
-
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. Nkx2.1 <superscript>Cre</superscript> ; Lkb1 <superscript>f/f</superscript> 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 Nkx2.1 <superscript>Cre</superscript> ; Lkb1 <superscript>f/f</superscript> 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 Nkx2.1 <superscript>Cre</superscript> ; Lkb1 <superscript>f/f</superscript> 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.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Cell Communication
Cell Line
Fibroblasts
Goblet Cells pathology
Humans
Lung pathology
Mice
Mice, Transgenic
AMP-Activated Protein Kinase Kinases physiology
AMP-Activated Protein Kinases physiology
Goblet Cells metabolism
Lung metabolism
Pulmonary Disease, Chronic Obstructive metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1420-9071
- Volume :
- 79
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cellular and molecular life sciences : CMLS
- Publication Type :
- Academic Journal
- Accession number :
- 34921639
- Full Text :
- https://doi.org/10.1007/s00018-021-04044-w