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

Kato, Kosuke; Lillehoj, Erik P.; Kim, Kwang Chul

doi:10.1165/rcmb.2014-0018oc

Cited by 32 publications

(26 citation statements)

References 29 publications

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“…Binding of MUC1 to TLR5 in airway epithelial cells prevents the recruitment of MyD88 to the intracellular tail, thereby inhibiting signaling and NF-κB activation [47,96]. MUC1 also inhibits signaling through TLR3 [97] and dampens TLR2 and TLR5 signaling in ocular epithelial cells [98]. MUC1 is part of a feedback loop that downregulates TLR2-induced IL-8 and TNF-α production after infection with nontypeable Haemophilus influenzae in airway epithelial cells [99].…”

Section: Regulation Of Inflammatory Responses By Transmembrane Mucinsmentioning

confidence: 99%

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

Putten¹,

Strijbis²

2017

J Innate Immun

208

213

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Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins.

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Section: Regulation Of Inflammatory Responses By Transmembrane Mucinsmentioning

confidence: 99%

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

Putten¹,

Strijbis²

2017

J Innate Immun

208

213

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“…16 In addition, production of the antiinflammatory IL-10 and type I interferon (IFN) has been shown to correlate with increased MUC1 expression. [17][18][19] Investigations in mice with Helicobacter pylori-induced gastritis revealed that Muc1 expression negatively regulates the NLRP3 inflammasome, which mediates production of IL-1b. 20 Taken together, these data suggest that in addition to a barrier role to infection, MUC1 may also be involved with regulation of inflammation in response to infection.…”

Section: Introductionmentioning

confidence: 99%

The cell surface mucin MUC1 limits the severity of influenza A virus infection

et al. 2017

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Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1 À / À mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.

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“…In gastric epithelia, MUC1 contributes to the physicochemical barrier against infectious pathogens (12). On airway epithelial cells, MUC1-EC is an adhesion site for Pseudomonas aeruginosa (Pa) (13,14), whereas MUC1-CT interacts with Toll-like receptors (TLRs) (15,16). Binding of MUC1-CT to TLR5 competitively inhibits recruitment of MyD88 to the TLR5 cytosolic Toll/IL-1 receptor domain, thereby suppressing TLR5 signaling and downstream inflammatory responses (15).…”

mentioning

confidence: 99%

Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages

Kato

Uchino

Lillehoj

et al. 2016

Am J Respir Cell Mol Biol

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MUC1 (MUC in human; Muc in animals) is a transmembrane mucin glycoprotein expressed in mucosal epithelial cells and hematopoietic cells. MUC1 is involved in the resolution of inflammation during airway Pseudomonas aeruginosa (Pa) infection by suppressing Toll-like receptor signaling in airway epithelial cells. Although alveolar macrophages are recognized as critical mediators of cell-mediated immunity against microorganisms inhaled into the airways, the role of MUC1 in regulating their response is unknown. The aims of this study were to determine whether macrophages express MUC1, and, if so, whether MUC1 expression might be associated with macrophage M0/M1/M2 differentiation or phagocytic activity. Human and mouse MUC1/Muc1 expression was drastically up-regulated in classically activated (M1) macrophages compared with nonactivated (M0) and alternatively activated (M2) macrophages. M1 polarization and Pa stimulation each increased MUC1 ectodomain shedding from the macrophage surface in a TNF-a-converting enzyme-dependent manner. MUC1/Muc1 deficiency in M0 macrophages increased adhesion and phagocytosis of Pa and Escherichia coli compared with MUC1/Muc1-expressing cells, and attenuation of phagocytosis by MUC1 was augmented after polarization into M1 macrophages compared with M0 macrophages. Finally, MUC1/Muc1 deficiency in macrophages increased reactive oxygen species production and TNF-a release in response to Pa compared with MUC1/Muc1-sufficient cells. These results indicate that MUC1/Muc1 expression by macrophages is predominantly in the M1 subtype, and that MUC1/Muc1 expression in these cells decreases their phagocytic activity in an antiinflammatory manner.

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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

Cited by 32 publications

References 29 publications

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

The cell surface mucin MUC1 limits the severity of influenza A virus infection

Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages

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