Lipopolysaccharide Disrupts the Milk-Blood Barrier by Modulating Claudins in Mammary Alveolar Tight Junctions

Kobayashi, Ken; Oyama, Shoko; Numata, Atsushi; Rahman, Md. Morshedur; Kumura, Haruto

doi:10.1371/journal.pone.0062187

Cited by 88 publications

(92 citation statements)

References 62 publications

(73 reference statements)

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“…Research shows that TLR4, and its ligand lipopolysaccharide (LPS), are both upregulated following irinotecan (26). This parallels other models of barrier dysfunction and supports the idea that TLR4 activation promotes barrier disruption (27,28).…”

Section: Introductionsupporting

confidence: 53%

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Wardill

Bowen

Sebille

et al. 2016

Molecular Cancer Therapeutics

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We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4−/−) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4−/− BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4−/− BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4−/− mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm2; P = 0.0008). No change was seen in Tlr4−/− mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4−/− mice at 24 hours (wild-type: 100.35 ± 18.37 μA/cm2; P = 0.022; Tlr4−/−: 102.72 ± 18.80 μA/cm2; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767–79. ©2016 AACR.

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Section: Introductionsupporting

confidence: 53%

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Wardill

Bowen

Sebille

et al. 2016

Molecular Cancer Therapeutics

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“…To visualize alveolar tight junction permeability, the animal was anaesthetised as above and 3 mg·mL À1 FITCconjugated albumin were used to treat the mammary glands as described (Kobayashi et al, 2013). Briefly, the mammary gland was removed and immersed in a solution containing 3 mg·mL À1 FITC-albumin for 10 min.…”

Section: Immunofluorescencementioning

confidence: 99%

Butyrate protects against disruption of the blood‐milk barrier and moderates inflammatory responses in a model of mastitis induced by lipopolysaccharide

Wang

Wei

Zhang

et al. 2017

British J Pharmacology

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Short-chain fatty acids are fermentation end products produced by gut bacteria, which have been shown to ameliorate inflammatory bowel diseases and allergic asthma. However, the mechanism involved remains largely unknown. Here, we investigate the protective effects and mechanisms of sodium butyrate (SB) on LPS-induced mastitis model. EXPERIMENTAL APPROACHEffects of increasing doses of SB on blood-milk barrier function and inflammation are studied in BALB/c mice with LPS-induced mastitis. The underlying mechanisms of anti-inflammatory effects of SB were further investigated in LPS-stimulated mouse mammary epithelial cells (mMECs). KEY RESULTSThe results show that SB decreased LPS-induced disruption in mammary tissues, infiltration of inflammatory cells and the levels of TNF-α, IL-6 and IL-1β. SB up-regulated the tight junction proteins occludin and claudin-3 and reduced blood-milk barrier permeability in LPS-induced mastitis. Studies in vitro revealed that SB inhibited LPS-induced inflammatory response by inhibition of the NF-κB signalling pathway and histone deacetylases in LPS-stimulated mMECs. CONCLUSIONS AND IMPLICATIONSIn our model, SB protected against LPS-induced mastitis by preserving blood-milk barrier function and depressing proinflammatory responses, suggesting the potential use of SB as a prophylactic agent to protect blood-milk barrier function in mastitis.

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“…We and Kobayashi showed previously that claudin-7 is present in alveolar cells at all stages of mammary development [29, 31] localized to basolateral surfaces as it is in many other tissues like the epididymis and intestine [30, 32, 33]. Recently, claudin-7 was shown to complex with EpCAM, an epithelial adhesion molecule enriched at the basolateral membrane of intestinal and other cells [34].…”

Section: Part 1 An Overview Of Claudin Structure and Biologymentioning

confidence: 99%

Developmental Expression of Claudins in the Mammary Gland

Baumgartner

Rudolph

Ramanathan

et al. 2017

J Mammary Gland Biol Neoplasia

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Claudins are a large family of membrane proteins whose classic function is to regulate the permeability of tight junctions in epithelia. They are tetraspanins, with four alpha-helices crossing the membrane, two extracellular loops, a short cytoplasmic N-terminus and a longer and more variable C-terminus. The extracellular ends of the helices are known to undergo side-to-side (cis) interactions that allow the formation of claudin polymers in the plane of the membrane. The extracellular loops also engage in head-to-head (trans) interactions thought to mediate the formation of tight junctions. However, claudins are also present in intracellular structures, thought to be vesicles, with less well-characterized functions. Here, we briefly review our current understanding of claudin structure and function followed by an examination of changes in claudin mRNA and protein expression and localization through mammary gland development. Claudins-1, 3, 4, 7, and 8 are the five most prominent members of the claudin family in the mouse mammary gland, with varied abundance and intracellular localization during the different stages of post-pubertal development. Claudin-1 is clearly localized to tight junctions in mammary ducts in non-pregnant non-lactating animals. Cytoplasmic puncta that stain for claudin-7 are present throughout development. During pregnancy claudin-3 is localized both to the tight junction and basolaterally while claudin-4 is found only in sparse puncta. In the lactating mouse both claudin-3 and claudin-8 are localized at the tight junction where they may be important in forming the paracellular barrier. At involution and under challenge by lipopolysaccharide claudins −1, −3, and −4 are significantly upregulated. Claudin-3 is still colocalized with tight junction molecules but is also distributed through the cytoplasm as is claudin-4. These largely descriptive data provide the essential framework for future mechanistic studies of the function and regulation of mammary epithelial cell claudins.Electronic supplementary materialThe online version of this article (doi:10.1007/s10911-017-9379-6) contains supplementary material, which is available to authorized users.

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Lipopolysaccharide Disrupts the Milk-Blood Barrier by Modulating Claudins in Mammary Alveolar Tight Junctions

Cited by 88 publications

References 62 publications

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Butyrate protects against disruption of the blood‐milk barrier and moderates inflammatory responses in a model of mastitis induced by lipopolysaccharide

Developmental Expression of Claudins in the Mammary Gland

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