Pivotal role of MUC1 glycosylation by cigarette smoke in modulating disruption of airway adherens junctions in vitro

BackgroundEfficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.ObjectiveTo explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.MethodsC57BL/6, BALB/c and IL-1RL1-/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls.ResultsWild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1-/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD.ConclusionsExposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

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Inhibition of salivary enzymes by cigarette smoke and the protective role of glutathione

Human & Experimental Toxicology ◽

10.1191/0960327102ht202oa ◽

2002 ◽

Vol 21 (1) ◽

pp. 7-11 ◽

Cited By ~ 48

Author(s):

B Zappacosta ◽

S Persichilli ◽

A Mordente ◽

A Minucci ◽

D Lazzaro ◽

...

Keyword(s):

Cigarette Smoke ◽

Tobacco Smoke ◽

Periodontal Diseases ◽

Lactic Dehydrogenase ◽

Protective Role ◽

Significant Inhibition ◽

Enzymatic Activities ◽

Enzyme Molecules

Tobacco smoke is involved in the pathogenesis of several diseases regarding different body systems, mainly cardiovascular and respiratory in addition to its local toxic effect in the oral cavity. The noxious effects of smoke compounds justify the high incidence of periodontal diseases, caries, and neoplastic diseases of oral tissues in smokers. Some toxic components of tobacco smoke, unsaturated and saturated aldehydes, could interact with thiol rich compounds, leading to structural and functional modification of these molecules. Previous papers have demonstrated an in vitro significant decrease of some enzymatic activities, both in plasma and in saliva, following external addition of aldehydes or exposure to cigarette smoke (CS). Furthermore, the same studies underlined the protective effect exerted by the addition of glutathione (GSH) against the damaging role of smoke aldehydes. In this study some salivary enzymes (lactic dehydrogenase [LDH], aspartate aminotransferase [AST] and amylase), and total GSH were measured in 20 volunteers smokers, before and just after smoking a single cigarette. All enzymatic activities showed a significant inhibition following a single cigarette, probably due to the interaction between smoke aldehydes and–SH groups of the enzyme molecules. Moreover, the percentage of the enzymatic inhibition showed a negative correlation with the basal level of salivary GSH. Our results emphasize that not only one cigarette is sufficient to impair the salivary enzymatic activities but also strengthen the proposed protective role of GSH against the noxious biochemical effects of CS.

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345 Cigarette smoke-induced endothelial dysfunction in vitro: Role of the cyclooxygenase pathway

Toxicology Letters ◽

10.1016/s0378-4274(03)90344-4 ◽

2003 ◽

Vol 144 ◽

pp. s94

Author(s):

R. Schleef ◽

K. von Holt

Keyword(s):

Endothelial Dysfunction ◽

Cigarette Smoke

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Pivotal role of the B7:CD28 pathway in transplantation tolerance and tumor immunity

Blood ◽

10.1182/blood.v84.10.3261.bloodjournal84103261 ◽

1994 ◽

Vol 84 (10) ◽

pp. 3261-3282 ◽

Cited By ~ 3

Author(s):

EC Guinan ◽

JG Gribben ◽

VA Boussiotis ◽

GJ Freeman ◽

LM Nadler

Keyword(s):

Immune Response ◽

Immune Function ◽

Tumor Immunity ◽

Clinical Applications ◽

Pivotal Role ◽

Transplantation Tolerance ◽

Clinical Potential

The above story illustrates the translation of basic scientific discoveries to the clinic. In vitro and preclinical in vivo experimentation suggests that modulation of the B7:CD28 pathway will result in either amplification or suppression of the immune response. Considering the frequency with which diseases characterized by either inadequate or dysregulated immune function present to the practicing hematologist or oncologist, it is not difficult to envisage clinical applications for reagents that modulate this pathway. However, we still have much to learn about the function and clinical potential of this and other potentially redundant costimulatory pathways and therefore we suspect that this story will become considerably more complex over the next few years.

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In vitro aspirin resistance detected by PFA-100TM closure time: pivotal role of plasma von Willebrand factor

British Journal of Haematology ◽

10.1046/j.1365-2141.2003.04727.x ◽

2003 ◽

Vol 124 (1) ◽

pp. 80-85 ◽

Cited By ~ 84

Author(s):

Tahar Chakroun ◽

Grigoris Gerotziafas ◽

Françoise Robert ◽

Chantal Lecrubier ◽

Meyer Michel Samama ◽

...

Keyword(s):

Von Willebrand Factor ◽

Aspirin Resistance ◽

Pivotal Role ◽

Closure Time ◽

Von Willebrand ◽

Willebrand Factor

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Pivotal role of the carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro

International Immunology ◽

10.1093/intimm/dxaa034 ◽

2020 ◽

Vol 32 (10) ◽

pp. 673-682 ◽

Cited By ~ 1

Author(s):

Junta Nasu ◽

Tomofumi Uto ◽

Tomohiro Fukaya ◽

Hideaki Takagi ◽

Takehito Fukui ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Line ◽

Glycosylation Site ◽

The Self ◽

Pivotal Role ◽

Carbohydrate Recognition Domain ◽

Carbohydrate Recognition ◽

Lectin Receptors

Abstract C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) with a characteristic carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces negative signals. However, how CLEC4A exerts cellular inhibition remains unclear. Here, we report that the self-interaction of CLEC4A through the CRD is required for the ITIM-mediated suppressive function in conventional dendritic cells (cDCs). Human type 2 cDCs (cDC2) and monocytes display a higher expression of CLEC4A than cDC1 and plasmacytoid DCs (pDCs) as well as B cells. The extracellular portion of CLEC4A specifically binds to a murine cDC cell line expressing CLEC4A, while its extracellular portion lacking the N-glycosylation site or the EPS motif within the CRD reduces their association. Furthermore, the deletion of the EPS motif within the CRD or ITIM in CLEC4A almost completely impairs its suppressive effect on the activation of the murine cDC cell line, whereas the absence of the N-glycosylation site within the CRD exhibits partial inhibition on their activation. On the other hand, antagonistic monoclonal antibody (mAb) to CLEC4A, which inhibits the self-interaction of CLEC4A and its downstream signaling in murine transfectants, enhances the activation of monocytes and monocyte-derived immature DCs upon stimulation with a Toll-like receptor (TLR) ligand. Thus, our findings suggest a pivotal role of the CRD in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory signal for the control of the function of cDCs.

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Divergent Effect of Cigarette Smoke on Innate Immunity in Inflammatory Bowel Disease: A Nicotine-Infection Interaction

International Journal of Molecular Sciences ◽

10.3390/ijms21165801 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5801 ◽

Cited By ~ 2

Author(s):

Dania AlQasrawi ◽

Ahmad Qasem ◽

Saleh A. Naser

Keyword(s):

Inflammatory Bowel Disease ◽

Cigarette Smoke ◽

Bowel Disease ◽

Mycobacterium Avium Subspecies Paratuberculosis ◽

Microbial Infection ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Inflammatory Phenotypes

Cigarette smoke (CS) has adverse effects in patients with Crohn’s disease (CD), an inflammatory bowel disease (IBD) that has been associated with microbial infection, immuno-dysregulation, and mucosal dysfunction. However, CS seems to provide relief and protection to patients with another IBD known as ulcerative colitis (UC). These two subsets are featured as M1- and M2-mediated responses, respectively. Nicotine is the most active, addictive, and studied ingredient in CS. The mechanism of how nicotine and/or other CS ingredients induce pro-inflammatory or anti-inflammatory phenotypes in IBD patients remains under investigation. Our most recent in vitro nicotine study provided significant insights toward understanding the contradictory effects of nicotine on IBD patients, and it elucidated the mechanistic role of α7nAChR in modulation of macrophages in tobacco smokers. Shifting the beneficial effect of nicotine to a harmful outcome in CD patients was linked to a nicotine-microbe interaction that supports a microbial etiology in CD pathogenesis. Among the most debated pathogens in CD etiology is Mycobacterium avium subspecies paratuberculosis (MAP). Other studies associated nicotine with upregulation of miR-124 expression in macrophages, which led to anti-inflammatory response. This review discusses published work on the role of nicotine in modulation of the innate immune response and subsequent signaling in macrophages in IBD subsets.

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