title: miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation.
abstract: Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Ruozhen
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Kagele
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Huffaker
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Marah C
authors.initials: MC
authors.lastname: Runtsch
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Bake
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Williams
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Möller
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA.
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.affiliation: Department of Pathology, Division of Microbiology and Immunology, University of Utah, 4280 JMRB, 15 North Medical Dr. East, Salt Lake City, UT 84112, USA. Electronic address: ryan.oconnell@path.utah.edu.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D051921:Fos-Related Antigen-2 / Q000235:genetics; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D056724:Immunity, Humoral; D007249:Inflammation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015704:CD4 Antigens; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse; D034741:RNA, Small Interfering