title: Interleukin-10 modulates antigen presentation by dendritic cells through regulation of NLRP3 inflammasome assembly during Chlamydia infection.
abstract: Interleukin-10 (IL-10) has been implicated in susceptibility to genital chlamydial infection and the development of tubal pathologies. IL-10 limitation also resulted in the rapid elicitation of immune responses against Chlamydia, and decreased levels of IL-10 correlated with protective anti-Chlamydia immunity. To investigate the molecular basis for these effects, we compared the reproductive pathologies and fertility rates in Chlamydia-infected wild-type (WT) and IL-10-knockout (IL-10(-/-)) mice; we also analyzed the expression of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily, IL-1β production, NLRP3 inflammasome assembly and activation, and the immunostimulatory capacity and apoptotic predilection of Chlamydia-exposed dendritic cells (DCs) from WT and IL-10(-/-) mice. Our results revealed that, in addition to the rapid clearance of infection, genitally infected IL-10(-/-) mice were protected from tubal pathologies and infertility, whereas WT (IL-10(+/+)) mice were not. Chlamydia-pulsed IL-10(-/-) DCs expressed larger numbers of TLR4/IL-1R molecules and had enhanced IL-1β production. In addition, NLRP3 inflammasome assembly was suppressed in IL-10(-/-) DCs through the inhibition of the P2X purinoceptor 7 (P2X7) receptor (P2X7R), an ATP-gated ion channel, and a decrease in intracellular Ca(2+) levels, which inhibited DC apoptosis. Thus, the potent immunostimulatory capacity of IL-10-deficient DCs is due, at least in part, to the suppression of the intracellular inflammasome assembly, which prevents DC apoptosis, allowing efficient antigen presentation. The results indicate that IL-10 deficiency enables efficient antigen presentation by DCs for rapid and enhanced immune activation against Chlamydia, which results in rapid microbial clearance, which prevents tubal pathologies during infection. Our finding has important implications for the induction of protective immunity against Chlamydia and other infectious and noninfectious diseases by vaccines.
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Omosun
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA Department of Biology, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: McKeithen
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA Department of Biology, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Khamia
authors.initials: K
authors.lastname: Ryans
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kibakaya
authors.affiliation: Department of Pathology, University of Georgia College of Veterinary Medicine, Athens, Georgia, USA.
authors.forename: Uriel
authors.initials: U
authors.lastname: Blas-Machado
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Neurology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Neurology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Eko
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Black
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Igietseme
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA Centers for Disease Control and Prevention, Atlanta, Georgia, USA qhe@msm.edu.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis / Q000276:immunology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D023502:Chlamydia muridarum / Q000276:immunology* / Q000472:pathogenicity; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D005260:Female; D005298:Fertility / Q000276:immunology*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C556062:IL10 protein, mouse; C583355:IL1R1 protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D058486:Receptors, Purinergic P2X7; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D002118:Calcium