Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice
Division of Rheumatology, Department of Medicine; Program in Innate Immunity; Division of Infectious Diseases and Immunology, Department of Medicine
Immunology and Infectious Disease | Rheumatology
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.
DOI of Published Version
J Immunol. 2016 Feb 1;196(3):1348-54. doi: 10.4049/jimmunol.1502130. Epub 2016 Jan 4. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Baum, Rebecca; Nundel, Kerstin; Pawaria, Sudesh; Sharma, Shrutie; Busto, Patricia; Fitzgerald, Katherine A.; Gravallese, Ellen M.; and Marshak-Rothstein, Ann, "Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice" (2016). University of Massachusetts Medical School Faculty Publications. 1171.