Higher susceptibility to experimental autoimmune encephalomyelitis in Muc1-deficient mice is associated with increased Th1/Th17 responses

Yen, Jui‐Hung; Xu, Shuyun; Park, Yong Sung; Ganea, Doina; Kim, Kwang Chul

doi:10.1016/j.bbi.2012.12.004

Cited by 14 publications

(16 citation statements)

References 39 publications

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“…Studies from various research groups, using wild-type (WT) and Muc1 −/− knockout mice, have shown MUC1 to be associated with an anti-inflammatory/immune-regulatory effect, analogous to other co-inhibitory molecules ( 70 – 72 ).…”

Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

“…Muc1 −/− mice were shown to develop greater experimental autoimmune encephalomyelitis (EAE) symptoms compared to wild-type (WT) mice, with increased numbers of Th1 and Th17 cells infiltrating into the CNS. It was shown that splenocytes from Muc1 −/− KO mice had greater amounts of IL-1β, IL-6, and IL-12 but lesser amounts of IL-10 production, compared to wild-type mice ( 72 ). It was also shown that splenocytes from Muc1 −/− KO mice, which were stimulated with anti-CD3 or anti-CD3 and anti-CD28, expressed higher levels of T-bet, ROR-γ and cytokines IFN-γ and IL-17, compared to WT mice.…”

Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

“…It was also shown that splenocytes from Muc1 −/− KO mice, which were stimulated with anti-CD3 or anti-CD3 and anti-CD28, expressed higher levels of T-bet, ROR-γ and cytokines IFN-γ and IL-17, compared to WT mice. However, purified T cells isolated from both Muc1 −/− and WT mice differentiated similarly to produce IFN-γ and IL-17, whereas DCs isolated from Muc1 −/− KO mice produced higher levels of inflammatory cytokines IL-1β, IL-12, and IL-6, and lower levels of IL-10, compared to WT mice ( 72 ). These results suggest that lack of Muc1 expression on T cells does not directly influence their ability to produce effector cytokines.…”

Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

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MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells

2018

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T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co-inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune check-points or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a “checkpoint molecule” of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections.

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Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

Section: Experimental Evidence Supporting the Role Of Muc1 As An Immumentioning

confidence: 99%

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MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells

2018

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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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“… Barrera et al found that TNF tended to increase the mRNA expression of MUC1 gene by mucin–cytokine signaling loop in inflammation environment. Interestingly, the anti‐inflammatory properties are observed in knockout mice of MUC1 gene . In patients with T2DM, low‐grade inflammation has been regarded to be a common characteristic; therefore, inflammation may increase the MUC1 gene expression in various kinds of cells in patients with T2DM.…”

Section: Discussionmentioning

confidence: 75%