Although inflammation is an essential host defense mechanism during lung infection, its timely resolution is critical for the host to prevent lung injuries resulting from uncontrolled inflammatory cells. Recently we discovered that MUC1, one of the membrane-tethered mucins expressed on the apical surface of airway epithelial cells, has an ability to control inflammation at the end of airway Pseudomonas aeruginosa (Pa) infection by suppressing toll-like receptor (TLR)5 signaling. In this renewal application, we propose to elucidate the mechanism by which MUC1 suppresses TLR5 during Pa infection. We hypothesize that MUC1 suppresses TLR5 signaling during Pa infection by a direct interaction with TLR5 which is mediated through activation of EGFR and propose the following aims to test the hypothesis.
In Aim 1, we will determine whether anti-inflammatory effect of MUC1 during airway Pa infection is due to its direct interaction with TLR5 by examining the details of molecular interactions between MUC1 and TLR5 in cultured epithelial cells using both genetic and immunological methods.
In Aim 2, we will determine whether the interaction of MUC1 with TLR5 is regulated by tyrosine phosphorylation of MUC1 by EGFR in cultured cells using genetic as well as immunological methods and such role of EGFR will be verified using EGFR deficient mice. In the final Aim 3, the complete sequence of the events that take place from Pa infection to the resolution of inflammation by MUC1 will be monitored in real time using both cultured cells and in vivo animals. Successful completion of these experiments will provide the detailed molecular interactions associated with the anti-inflammatory role of MUC1 during airway Pa infection and should provide insights into possible therapeutic strategies to control excessive and prolonged lung inflammation characteristic of chronic inflammatory lung diseases such as COPD and cystic fibrosis.

Public Health Relevance

Chronic lung inflammatory diseases such as COPD, asthma and cystic fibrosis develop as a result of failure to control lung inflammation in a timely manner. MUC1 is a new anti- inflammatory molecule that prevents excessive inflammation during airway infection. Understanding how MUC1 controls excessive lung inflammation will help us to better understand the pathophysiology of these lung diseases and may provide insights into possible therapeutic strategies to treat these inflammatory lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Punturieri, Antonello
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Temple University
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Kato, Kosuke; Lillehoj, Erik P; Kim, Kwang Chul (2016) Pseudomonas aeruginosa stimulates tyrosine phosphorylation of and TLR5 association with the MUC1 cytoplasmic tail through EGFR activation. Inflamm Res 65:225-33
Kato, Kosuke; Uchino, Reina; Lillehoj, Erik P et al. (2016) Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages. Am J Respir Cell Mol Biol 54:515-23
Kato, Kosuke; Lillehoj, Erik P; Kim, Kwang Chul (2014) MUC1 regulates epithelial inflammation and apoptosis by PolyI:C through inhibition of Toll/IL-1 receptor-domain-containing adapter-inducing IFN-β (TRIF) recruitment to Toll-like receptor 3. Am J Respir Cell Mol Biol 51:446-54
Yen, Jui-Hung; Xu, Shuyun; Park, Yong Sung et al. (2013) Higher susceptibility to experimental autoimmune encephalomyelitis in Muc1-deficient mice is associated with increased Th1/Th17 responses. Brain Behav Immun 29:70-81
Lillehoj, Erik P; Kato, Kosuke; Lu, Wenju et al. (2013) Cellular and molecular biology of airway mucins. Int Rev Cell Mol Biol 303:139-202
Kato, Kosuke; Lillehoj, Erik P; Park, Yong Sung et al. (2012) Membrane-tethered MUC1 mucin is phosphorylated by epidermal growth factor receptor in airway epithelial cells and associates with TLR5 to inhibit recruitment of MyD88. J Immunol 188:2014-22
Umehara, Tsuyoshi; Kato, Kosuke; Park, Yong Sung et al. (2012) Prevention of lung injury by Muc1 mucin in a mouse model of repetitive Pseudomonas aeruginosa infection. Inflamm Res 61:1013-20
Park, Yong Sung; Lillehoj, Erik P; Kato, Kosuke et al. (2012) PPARýý inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 302:L679-87
Kyo, Yoshiyuki; Kato, Kosuke; Park, Yong Sung et al. (2012) Antiinflammatory role of MUC1 mucin during infection with nontypeable Haemophilus influenzae. Am J Respir Cell Mol Biol 46:149-56
Kim, Kwang Chul (2012) Role of epithelial mucins during airway infection. Pulm Pharmacol Ther 25:415-9

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