STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice

Abstract

Objective Cytosolic DNA sensors detect microbial DNA and promote type I interferon and pro-inflammatory cytokine production through the adaptor stimulator of interferon genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. We identified a novel role for STING in bone in arthritic DNase II/IFNaR double deficient (DKO) mice, and sought to define the bone phenotype in these mice and to address mechanism. Methods Bone parameters were evaluated in DKO, STING/DNaseII/IFNaR triple deficient and control mice by microcomputed tomography and histomorphometry. Cell culture techniques were employed to determine parameters of osteoclast and osteoblast differentiation and function. Nanostring and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation. Results Despite the expression of pro-inflammatory cytokines that would be expected to induce bone loss in the skeleton in DKO mice, we demonstrate the paradoxical accumulation of bone in the long bones and spleen, sites of erythropoiesis and robust DNA accrual, as well as the induction of factors promoting osteoblast recruitment and function. STING deficiency significantly inhibits this bone accrual. Conclusions These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. We demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in autoimmune diseases.

A STING to inflammation and autoimmunity

“…The deficiency of DNase II, an enzyme localized in lysosomes that clears DNA of dead cells and DNA expelled from nuclei, also increases the activation of STING signaling and the generation of type 1 IFNs causing systemic autoinflammation . The STING signaling is also responsible for the acrid bone accumulation in the long bones and spleens, sites of erythropoiesis, and the potent DNA accrual in DNase II/IFNaR double deficient (double knockout [DKO]) mice . The STING signaling in the DKO mice also induces the factors responsible for the recruitment and function of osteoblasts to induce erosive inflammatory arthritis (EIA) .…”

“…The STING signaling is also responsible for the acrid bone accumulation in the long bones and spleens, sites of erythropoiesis, and the potent DNA accrual in DNase II/IFNaR double deficient (double knockout [DKO]) mice . The STING signaling in the DKO mice also induces the factors responsible for the recruitment and function of osteoblasts to induce erosive inflammatory arthritis (EIA) . The deletion of STING completely abrogated the EIA .…”

“…The STING signaling in the DKO mice also induces the factors responsible for the recruitment and function of osteoblasts to induce erosive inflammatory arthritis (EIA) . The deletion of STING completely abrogated the EIA . The deletion of cGAS in DNase II −/− in mice rescues the development of systemic autoinflammation and autoimmune phenotype by preventing the accumulation of cGAMP and dependent STING‐mediated expression of ISGs and type 1 IFNs .…”

Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING-Mediated Interferon-β Signaling

“…(44) In contrast, STING deficiency inhibits bone accrual due to attenuation of pro-osteogenic gene expression. (45) Collectively, we propose that targeting the STING signaling pathway in the early stage of osteoclast differentiation by CDNs is a novel strategy for regulation of osteoclastogenesis.…”

Interplay of Cyclic GMP-AMP Synthase/Stimulator of IFN Genes and Toll-Like Receptor Nucleic Acid Sensing Pathways in Autoinflammation and Abnormal Bone Formation due to DNaseII-Deficiency

“…Microcomputed tomography (micro-CT) and radiography were performed and quantified as described previously (5).…”