title: Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways.
abstract: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term "memory." In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostat mechanism, which enables macrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15220, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: INRIA, Campus de Beaulieu, 35042 Rennes, France.
authors.forename: Sucheendra K
authors.initials: SK
authors.lastname: Palaniappan
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15220, USA.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
authors.affiliation: Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. thiagu@hms.harvard.edu dbsdjl@nus.edu.sg.
authors.forename: P S
authors.initials: PS
authors.lastname: Thiagarajan
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore. thiagu@hms.harvard.edu dbsdjl@nus.edu.sg.
authors.forename: Jeak Ling
authors.initials: JL
authors.lastname: Ding
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006706:Homeostasis / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D007156:Immunologic Memory / Q000502:physiology*; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018448:Models, Immunological; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; D050791:STAT Transcription Factors; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D053612:Janus Kinases