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. Here we utilize 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 Toll-like receptors (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.

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

“…However, despite the findings of local and systemic production of TNF, IL-1b, and IL-6 (which promote osteoclastogenesis), there was a surprising and significant accrual of trabecular bone in the tibiae adjacent to the inflamed ankle joints of DKO mice as compared with Het control mice ( Figure 1B). This trabecular bone formation occurred despite the presence of an increased number of TRAP-expressing osteoclasts in DKO mice ( Figure 1B), and was preceded by a marrow infiltrate that we have previously shown to be dependent on the expression of both the STING and endosomal TLR pathways (32).…”

“…The inability, in DKO mice, to degrade DNA eventually leads to infiltration of DNA into cytosolic compartments and activation of cytosolic DNA sensors that converge on STING. In addition, the ensuing inflammation and cell death most likely lead to the release of ligands that can engage endosomal TLRs, which have been implicated in both autoantibody formation and splenomegaly in these mice . These pathways may contribute to bone formation in this model as well.…”

Taking the STING out of TLR-driven autoimmune diseases: good, bad, or indifferent?

“…Through the use of radiation chimeras, we further showed that both DNaseII 2/2 hematopoietic and DNaseII 2/2 radioresistant cells are absolutely required for the development of arthritis in this model, as neither DKO→Het nor Het→DKO chimeras show any clinical or histologic evidence of joint inflammation, whereas DKO→DKO chimeras completely replicate the original DKO clinical phenotype [41] (summarized in Table 2). The nature of the radioresistant cell(s) and the relevant sensor in each of these cell types (STING, AIM2, or additional receptors) remain to be determined, but these studies demonstrate synergy between hematopoietic and nonhematopoietic cells in NA sensorinduced inflammation.…”

The many ways tissue phagocytes respond to dying cells

“…261 DNASE2 deficiency in both the hematopoietic and stromal compartment is required for the development of arthritis in these mice. 263 Deletion of TLR3, TLR9 or both TLR signaling adapters TRIF and MyD88, did not impact the lethality of DNASE2-deficient mice suggesting that the interferon response is mediated by a TLR-independent mechanism. 264 Analysis of DNASE2-deficient mouse fetuses showed liver and spleen accumulation of cyclic dinucleotide [G(2′,5′)pA(3′,5′)p] (2′,3′-cGAMP), the product of the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS).…”

“…This phenotype is a result of TNF-α production by macrophages unable to degrade apoptotic cell DNA (260). DNASE2 deficiency in both the hematopoietic and stromal compartment is required for the development of arthritis in these mice (262). Deletion of TLR3, TLR9 or both TLR signaling adaptors TRIF and MyD88, did not impact the lethality of DNASE2 deficient mice suggesting that the interferon response is mediated by a TLR-independent mechanism (263).…”