2019
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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… Show more

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“…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 ).…”
Section: Discussionmentioning
“…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.…”
Section: Resultsmentioning
“…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).…”
Section: Introductionmentioning
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“…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 ].…”
Section: Mechanisms Of Efferocytosismentioning