title: Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice.
abstract: Detection of endogenous nucleic acids by cytosolic receptors, dependent on STING, and endosomal sensors, dependent on Unc93b1, can provoke inflammatory responses that contribute to a variety of autoimmune and autoinflammatory diseases. In DNase II-deficient mice, the excessive accrual of undegraded DNA leads to both a STING-dependent inflammatory arthritis and additional Unc93b1-dependent autoimmune manifestations, including splenomegaly, extramedullary hematopoiesis, and autoantibody production. In this study, we use bone marrow chimeras to show that clinical and histological inflammation in the joint depends upon DNase II deficiency in both donor hematopoietic cells and host radioresistant cells. Additional features of autoimmunity in these mice, known to depend on Unc93b1 and therefore endosomal TLRs, also require DNase II deficiency in both donor and host compartments, but only require functional TLRs in the hematopoietic cells. Collectively, our data demonstrate a major role of both stromal and hematopoietic cells in all aspects of DNA-driven autoimmunity. These findings further point to the importance of cytosolic nucleic acid sensors in creating an inflammatory environment that facilitates the development of Unc93b1-dependent autoimmunity.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Rebecca
authors.identifier: http://orcid.org/0000-0002-7766-3422
authors.initials: R
authors.lastname: Baum
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nündel
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Sudesh
authors.initials: S
authors.lastname: Pawaria
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Busto
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and ann.rothstein@umassmed.edu.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000276:immunology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D026901:Membrane Transport Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D017154:Stromal Cells / Q000276:immunology*; D000099197:STING Protein
chemical_list: D004706:Endodeoxyribonucleases; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C512254:UNC93B1 protein, mouse; C019329:deoxyribonuclease II