P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

Woods, Lucas T.; Camden, Jean M.; Batek, Josef; Petris, Michael J.; Erb, Laurie; Weisman, Gary A.

doi:10.1152/ajpcell.00072.2012

Cited by 54 publications

(54 citation statements)

References 109 publications

(226 reference statements)

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“…Therefore the IFN-γ −/− CD28 −/− mouse model provides a unique tool for investigating mechanisms involved in SS development. The extent to which this model compares to other mouse models of SS (30, 57, 58, 63) remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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60–70 % of IFN-γ−/− NOD.H-2h4 mice given NaI-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell hyperplasia/ proliferation (TEC H/P). TEC H/P develops much earlier in CD28−/− mice and nearly 100 % (both sexes) have severe TEC H/P at 4 months of age. Without NaI supplementation, 50% of 5–6 month old CD28−/−IfFN-γ−/− mice develop severe TEC H/P, and 2–3 weeks of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid and normalization of serum thyroxine (T4) levels does not reduce TEC H/P. Activated CD4+ T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for development of severe TEC H/P, as CD40−/−IFN-γ−/−CD28−/− mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ−/− CD28−/− mice is a result of reduced Treg numbers as CD28−/− mice have significantly fewer Tregs, and transfer of CD28-positive Tregs inhibits TEC H/P. Essentially all female IFN-γ−/− CD28−/−NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 months of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 months of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.

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Section: Discussionmentioning

confidence: 99%

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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“…ATP via P2X7 receptors increased the production of reactive oxygen species in rat submandibular glands, and the authors speculate that purinergic receptors could be regulators of the bactericidal properties of saliva by promoting the secretion of peroxidase from acinar cells and by activating Duox2 [226]. It was reported that P2X7 receptor activation induces inflammatory responses in mouse submandibular gland cells [714].…”

Section: Submandibular Glandmentioning

confidence: 99%

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Burnstock

2013

Purinergic Signalling

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Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in nonadrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.

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“…In combination with widespread actions of ATP, P2X receptors, expressed on virtually every cell type [1], play essential roles in the body [2]. Thus, it is not surprising that P2X receptors mediate many physiological and pathological processes including synaptic transmission [3]-[7], pain signalling [8], the immune response [9]-[11], taste [12] and bone formation [13], which makes them attractive targets for drug discovery [14]-[18].…”

Section: Introductionmentioning

confidence: 99%

Functional Identification of Close Proximity Amino Acid Side Chains within the Transmembrane-Spanning Helixes of the P2X2 Receptor

Liang

et al. 2013

PLoS ONE

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The transition from the closed to open state greatly alters the intra- and inter-subunit interactions of the P2X receptor (P2XR). The interactions that occur in the transmembrane domain of the P2X2R remain unclear. We used substituted cysteine mutagenesis disulfide mapping to identify pairs of residues that are in close proximity within the transmembrane domain of rP2X2R and compared our results to the predicted positions of these amino acids obtained from a rat P2X2R homology model of the available open and closed zebrafish P2X4R structures. Alternations in channel function were measured as a change in the ATP-gated current before and after exposure to dithiothreitol. Thirty-six pairs of double mutants of rP2X2R expressed in HEK293 cells produced normal functioning channels. Thirty-five pairs of these mutants did not exhibit a functionally detectable disulfide bond. The double mutant H33C/S345C formed redox-dependent cross-links in the absence of ATP. Dithiothreitol ruptured the disulfide bond of H33C/S345C and induced a 2 to 3-fold increase in current. The EC50 for H33C/S345C before dithiothreitol treatment was ∼2-fold higher than that after dithiothreitol treatment. Dithiothreitol reduced the EC50 to wild-type levels. Furthermore, expression of trimeric concatamer receptors with Cys mutations at some but not all six positions showed that the more disulfide bond formation sites within the concatamer, the greater current potentiation after dithiothreitol incubation. Immunoblot analysis of H33C/S345C revealed one monomer band under nonreducing conditions strongly suggesting that disulfide bonds are formed within single subunits (intra-subunit) and not between two subunits (inter-subunit). Taken together, these data indicate that His33 and Ser345 are proximal to each other across an intra-subunit interface. The relative movement between the first transmembrane and the second transmembrane in the intra-subunit is likely important for transmitting the action of ATP binding to the opening of the channel.

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P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

Cited by 54 publications

References 109 publications

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Functional Identification of Close Proximity Amino Acid Side Chains within the Transmembrane-Spanning Helixes of the P2X2 Receptor

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