MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli

Sheng, Yonghua; Triyana, Shofyatul Y.; Wang, Ran; Das, Indrajit; Gerloff, Kirsten; Florin, Timothy H.; Sutton, Philip; McGuckin, Michael A.

doi:10.1038/mi.2012.98

Cited by 119 publications

(103 citation statements)

References 34 publications

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“…Furthermore, we contend that upon interaction of IAV with the extracellular domain of MUC1, this subunit is released, extruding the virion into the lumen, while the cytoplasmic subunit is involved in signaling pathways that may lead to regulation of inflammatory mediators. 34 Further supporting a role for MUC1 in innate host-defences against infection, our in vivo infection studies revealed that Muc1 À / À mice were more vulnerable than WT mice to disease caused by the laboratory mouse adapted PR8 IAV and a 2009 H1N1 pandemic human IAV isolate, presumably resulting from increased viral burden early after infection and dysregulated inflammatory responses. MUC1 is expressed by virtually all of the surface columnar epithelial cells of the respiratory tract, as well as type II pneumocytes in the alveoli, 35 a major target of IAV infection.…”

Section: Discussionsupporting

confidence: 52%

“…For example, in response to TLR ligands, Muc13 in gastric mucosa enhances epithelial cell inflammatory cell signaling, the opposing function of Muc1 in the same tissue. 34 However, experiments with mice lacking Muc13 show this csmucin protects against intestinal inflammation in the colitis model, by inhibiting toxin-induced colonic epithelial cell apoptosis. 45,46 Loss of Muc16 caused upregulation of IL-6 in the mouse cornea affecting epithelium and stroma homeostasis.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…These findings suggest that PGEC are relevant for study of H. pylori infection. Compared to AGS cells, PGEC expressed higher levels of the proteins MUC1 and TFF1, both of which play an important role in regulation of inflammatory signaling (23,24). Most notably, it was shown that MUC1 regulates CXCL8 production by gastric epithelial cells in response to H. pylori (23).…”

Section: Discussionmentioning

confidence: 99%

“…Compared to AGS cells, PGEC expressed higher levels of the proteins MUC1 and TFF1, both of which play an important role in regulation of inflammatory signaling (23,24). Most notably, it was shown that MUC1 regulates CXCL8 production by gastric epithelial cells in response to H. pylori (23). The aim of this work was to provide a comparative inflammatory profile study involving PGEC and AGS cells after H. pylori infection.…”

Section: Discussionmentioning

confidence: 99%

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

et al. 2014

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e Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-␣). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128⌬cagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.

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“…MUC1 in gastric epithelial cells acted as a releasable decoy receptor against Helicobacter pylori that limited bacterial infection (32) and attenuated H. pylori-driven proinflammatory cytokine release (33,34). In other studies, whereas both MUC1 and MUC16 were expressed in corneal epithelial cells, only MUC16 provided a barrier to bacterial adherence (35).…”

Section: Muc1/muc1 Deficiency Enhances Ros Production and Tnf-a Releamentioning

confidence: 95%

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 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli

Cited by 119 publications

References 34 publications

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

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

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

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

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