Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice
Wenju Lu1, Akinori Hisatsune, Takeshi Koga
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 21201, USA.
Abstract:
MUC1 (MUC1 in human and Muc1 in nonhumans) is a membrane-tethered mucin that interacts with Pseudomonas aeruginosa (PA) through flagellin. In this study, we compared PA pulmonary clearance and proinflammatory responses by Muc1(-/-) mice with Muc1(+/+) littermates following intranasal instillation of PA or flagellin. Compared with Muc1(+/+) mice, Muc1(-/-) mice showed increased PA clearance, greater airway recruitment of neutrophils, higher levels of TNF-alpha and KC in bronchoalveolar lavage fluid, higher levels of TNF-alpha in media of flagellin-stimulated alveolar macrophages, and higher levels of KC in media of tracheal epithelial cells. Knockdown of MUC1 enhanced flagellin-induced IL-8 production by primary human bronchial epithelial cells. Expression of MUC1 in HEK293T cells attenuated TLR5-dependent IL-8 release in response to flagellin, which was completely ablated when its cytoplasmic tail was deleted. We conclude that MUC1/Muc1 suppresses pulmonary innate immunity and speculate its anti-inflammatory activity may play an important modulatory role during microbial infection.
Insights
Mucin 1 (MUC1) suppresses lung immunity against Pseudomonas aeruginosa. Mice lacking MUC1 cleared bacteria faster and showed heightened inflammatory responses, suggesting MUC1
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Mucin 1 (MUC1) is a membrane-tethered mucin involved in host-pathogen interactions.
- Pseudomonas aeruginosa (PA) utilizes flagellin to interact with host cells.
- The role of MUC1 in pulmonary innate immunity against PA infection is not fully understood.
Purpose of the Study:
- To investigate the role of MUC1 in Pseudomonas aeruginosa pulmonary clearance.
- To compare the proinflammatory responses in MUC1-deficient versus wild-type mice.
- To elucidate the mechanism by which MUC1 modulates innate immune responses to flagellin.
Main Methods:
- Intranasal instillation of PA or flagellin in Muc1(-/-) and Muc1(+/+) mice.
- Assessment of bacterial clearance and inflammatory cell recruitment (neutrophils).
- Measurement of cytokine levels (TNF-alpha, KC, IL-8) in bronchoalveolar lavage fluid and cell culture supernatants.
- In vitro studies using primary human bronchial epithelial cells and HEK293T cells with MUC1 knockdown or deletion of its cytoplasmic tail.
Main Results:
- Muc1(-/-) mice exhibited increased PA pulmonary clearance compared to Muc1(+/+) mice.
- Muc1(-/-) mice showed enhanced neutrophil recruitment and higher levels of TNF-alpha and KC in the lungs.
- MUC1 expression attenuated flagellin-induced IL-8 production in human bronchial epithelial cells and HEK293T cells, an effect dependent on its cytoplasmic tail.
Conclusions:
- MUC1/Muc1 suppresses pulmonary innate immunity.
- MUC1 acts as a negative regulator of the inflammatory response to Pseudomonas aeruginosa flagellin.
- The anti-inflammatory activity of MUC1 may modulate host defense during microbial infections.
