title: Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells.
abstract: The conjunctiva is a moist mucosal membrane that is constantly exposed to an array of potential pathogens and triggers of inflammation. The NACHT, leucine rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) is a Nod-like receptor that can sense pathogens or other triggers, and is highly expressed in wet mucosal membranes. NLRP3 is a member of the multi-protein complex termed the NLRP3 inflammasome that activates the caspase 1 pathway, inducing the secretion of biologically active IL-1β, a major initiator and promoter of inflammation. The purpose of this study was to: (1) determine whether NLRP3 is expressed in the conjunctiva and (2) determine whether goblet cells specifically contribute to innate mediated inflammation via secretion of IL-1β. We report that the receptors known to be involved in the priming and activation of the NLRP3 inflammasome, the purinergic receptors P2X4 and P2X7 and the bacterial Toll-like receptor 2 are present and functional in conjunctival goblet cells. Toxin-containing Staphylococcus aureus (S. aureus), which activates the NLRP3 inflammasome, increased the expression of the inflammasome proteins NLRP3, ASC and pro- and mature caspase 1 in conjunctival goblet cells. The biologically active form of IL-1β was detected in goblet cell culture supernatants in response to S. aureus, which was reduced when the cells were treated with the caspase 1 inhibitor Z-YVAD. We conclude that the NLRP3 inflammasome components are present in conjunctival goblet cells. The NRLP3 inflammasome appears to be activated in conjunctival goblet cells by toxin-containing S. aureus via the caspase 1 pathway to secrete mature IL1-β. Thus goblet cells contribute to the innate immune response in the conjunctiva by activation of the NLRP3 inflammasome.
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America ; Centre for Molecular Biosciences, University of Ulster, Coleraine, N. Ireland.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: McGilligan
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Gregory-Ksander
authors.forename: Dayu
authors.initials: D
authors.lastname: Li
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Moore
authors.forename: Robin R
authors.initials: RR
authors.lastname: Hodges
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gilmore
authors.forename: Tara C B
authors.initials: TC
authors.lastname: Moore
authors.forename: Darlene A
authors.initials: DA
authors.lastname: Dartt
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003228:Conjunctiva / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D020397:Goblet Cells / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D051195:Toll-Like Receptor 2; D000255:Adenosine Triphosphate; D020170:Caspase 1
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