Role of Interferon‐γ–Producing Th1 Cells in a Murine Model of Type I Interferon–Independent Autoinflammation Resulting From DNase II Deficiency

Abstract

Objective. Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DNase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response.Methods. To avoid embryonic death, Dnase2 −/− mice were intercrossed with mice that lacked the type I interferon (IFN) receptor (Ifnar −/− ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme-linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2 −/− × Ifnar −/− double-knockout (DKO) mice into Rag1 −/− mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice.Results. In Dnase2 −/− × Ifnar −/− DKO mice, many of the disease features found in DNase II-deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2 +/+ × Rag1 −/− mice (n > 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFNγ-producing T cell subset from the spleens of donor Dnase2 −/− × Ifnar −/− DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes (STING) pathway but was highly dependent on the chaperone protein Unc93B1.Conclusion. Dnase2 −/− × Ifnar −/− DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE2-hypomorphic patients. In this murine model, IFNγ is required for T cell activation and the development of clinical manifestations. The role of IFNγ in DNASE2-deficient patient populations remains to be determined, but the ability of Dnase2 −/− mouse T cells to transfer disease to Rag1 −/− mice suggests that T cells may be a relevant therapeutic target in patients with IFN-related systemic autoinflammatory diseases.

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

“…The ensuing accumulation of DNA in endosomal compartments of these cells could then enhance TLR dependent cytokine production through a cell intrinsic mechanism. DNAse II-deficient mice provide another example of excessive DNA accrual leading to the activation of multiple nucleic acid sensing pathways since the cGAS-STING, AIM2, and endosomal TLRs all have been shown to contribute to the development of autoimmunity or autoinflammation in this model ( 16 , 55 , 56 ). It is also possible that different DNA sensors may function in tissue specific manner for instance cGAS STING pathway can still contribute to certain aspects of disease such as the cutaneous lupus features as suggested by Skopelja-Gardner et al ( 20 ).…”

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

“…Moreover, these data clearly demonstrate that autoinflammation, even in monogenic diseases, can result from the activation of numerous NA sensors. Both patients and DKO mice, but not Unc93b1 TKO mice also develop liver fibrosis (21,24), but the role of STING in liver fibrosis has not yet been explored. A better understanding of the precise pathways activated in DNaseII-deficient cells-macrophages, granulocytes, dendritic cells, osteoblasts, fibroblast, and endothelial cellscould, therefore, reveal important new therapeutic targets for intervention in inflammatory diseases.…”

“…Trex1-deficient patients and mice exhibit nonoverlapping clinical manifestations; the central nervous system is frequently targeted in patients, whereas the heart is targeted in B6 mice. In contrast, there are remarkable similarities between patients with hypomorphic mutations in DNaseII and DNaseII-deficient mice (3,21,24).…”

“…These include anemia, cytopenia, extramedullary hematopoiesis associated with massive splenomegaly, elevated levels of proinflammatory serum cytokines, the production of antinuclear autoantibodies, and lymphocyte activation, all features that are absent from DNaseII +/-(heterozygous) IFNaR -/-(Het) controls (3,21). These SLE-like autoimmune manifestations are found in very young DKO mice and are dramatically decreased in DKO mice that inherit a functionally inactive form of the endosomal TLR chaperone protein Unc93b1 (Unc93b1 triple knockout, TKO), but not decreased in STING -/-DNaseII -/-IFNaR -/-TKO mice (21). Together these data identify clinical manifestations that depend on either STING (arthritis) or endosomal TLRs (cytopenia, splenomegaly/extramedullary hematopoiesis, and autoantibody production), but not both.…”

Metabolic Consequences of Efferocytosis and Its Impact on Atherosclerosis

“…Importantly, clearance of AC-derived DNA is critical for efferocytosis to remain non-phlogistic. Phagocytes incapable of degrading DNA within phagolysosomes cause a type-1 interferon response by activating intracellular nucleic acid sensors, leading to autoimmunity [ 38 , 39 ]. Importantly, disruption in any step of the efferocytosis program causes many chronic inflammatory diseases [ 4 ].…”