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Updated: Sep 16, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
MTMR14 depletion aggravates intrapulmonary inflammation and emphysema in experimental COPD through activating
Jiaheng Zhang1, Yuan Zhan2, Zhesong Deng1
1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Background:
Chronic obstructive pulmonary disease (COPD) is typically characterized by chronic airway inflammation and emphysema. Macrophage polarization plays an important role in COPD, while the precise molecules and mechanisms underpinning it have yet to be fully elucidated. Pulmonary decrease of myotubularin-related protein 14 (MTMR14) expression conduces to the progression of COPD in our prior publication, while the further analysis reveals the differential expression of MTMR14 in alveolar macrophages, whose function and related mechanisms are worth further research. Our study aims to investigate the role and mechanism of MTMR14 in macrophages of COPD.
Methods:
The expression and potential role of MTMR14 in COPD macrophages was explored via bioinformatic analysis and clinical detection, as well as in vivo and vitro experiments. By constructing animal model with Mtmr14 knockout and cell model with the knockdown or over-expression of MTMR14, the effect of MTMR14 on polarization direction of macrophages and the related signaling pathways were elaborated. Indirect co-culture was performed to probe the influence of MTMR14 in the crosstalk between macrophages and alveolar epithelium. The regulation of ubiquitin-proteasome system on MTMR14 expression was investigated via (co-)immunoprecipitation and cycloheximide chase assay.
Results:
Based on analysis from open-access single-cell sequencing data, MTMR14 was down-regulated in macrophages of COPD patients, which was confirmed in clinical specimens, animal and cell models. Meanwhile, MTMR14 was functionally enriched in inflammatory response and macrophage activation. Correspondingly, the knockout of MTMR14 aggravated the pulmonary function decline, emphysema, inflammation and pro-inflammatory macrophage polarization in mice exposed by cigarette smoke (CS). Mechanically, MTMR14 negatively regulated the M1 polarization of macrophages under CS extract (CSE)-stimulation through PI3K/Akt and NF-κB pathways. In addition, damage from macrophages on alveolar epithelium was intensified by the down-regulation of MTMR14 in the formation of emphysema. Finally, TRIM21 was found to down-regulate MTMR14 through ubiquitin-proteasome system in CSE-stimulated macrophages.
Conclusions:
Our findings underscore the mitigative role of MTMR14 on macrophage polarization towards pro-inflammatory phenotype, offering a promising target for prevention and intervention for COPD in clinical settings.
Clinical Trial Number:
Not applicable.
Insights
Myotubularin-related protein 14 (MTMR14) mitigates pro-inflammatory macrophage polarization in chronic obstructive pulmonary disease (COPD). Lower MTMR14 levels worsen COPD symptoms and emphysema, highlighting its therapeutic potential.
Area of Science:
- Pulmonary medicine
- Immunology
- Cell biology
Background:
- Chronic obstructive pulmonary disease (COPD) involves airway inflammation and emphysema, with macrophage polarization playing a key role.
- Myotubularin-related protein 14 (MTMR14) expression is decreased in COPD, particularly in alveolar macrophages, necessitating further investigation into its function.
- Prior studies indicated MTMR14's role in COPD progression, prompting this research into its specific mechanisms within macrophages.
Purpose of the Study:
- To investigate the role and underlying mechanisms of MTMR14 in macrophages relevant to COPD pathogenesis.
- To elucidate how MTMR14 influences macrophage polarization and inflammatory responses in the context of COPD.
- To identify potential therapeutic targets for COPD based on MTMR14's function.
Main Methods:
- Bioinformatic analysis, clinical detection, and in vivo/vitro experiments were employed to study MTMR14 in COPD macrophages.
- Animal models with Mtmr14 knockout and cell models with MTMR14 knockdown/overexpression were used to assess its functional impact.
- Signaling pathways (PI3K/Akt, NF-κB), macrophage-epithelium crosstalk, and ubiquitin-proteasome system regulation of MTMR14 were investigated.
Main Results:
- MTMR14 was found to be downregulated in macrophages of COPD patients, confirmed across various models.
- MTMR14 knockout exacerbated pulmonary dysfunction, emphysema, and M1 macrophage polarization in a mouse model of COPD.
- MTMR14 negatively regulated M1 polarization via PI3K/Akt and NF-κB pathways, and TRIM21 was identified as a negative regulator of MTMR14 via the ubiquitin-proteasome system.
Conclusions:
- MTMR14 plays a crucial role in mitigating the polarization of macrophages towards a pro-inflammatory phenotype in COPD.
- Downregulation of MTMR14 contributes to emphysema progression and alveolar epithelial damage.
- MTMR14 represents a promising therapeutic target for the prevention and intervention of COPD.
