Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

Kawane, Kohki; Tanaka, Hiromi; Kitahara, Yusuke; Shimaoka, Shin; Nagata, Shinji

doi:10.1073/pnas.1010603107

Cited by 97 publications

(89 citation statements)

References 42 publications

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“…Moreover, DNase II −/− Sting −/− do not exhibit signs of arthritis, similar to DNase II −/− Ifnar1 −/− mice (5, 7). Self-apoptotic DNA-triggered arthritis in such animals has been reported to be reminiscent of idiopathic arthritis or Still's disease in humans (18). STING has also been shown to rescue Trex1-mediated inflammation-related disorders in Trex1 −/− mice by mechanisms that remain unknown (19).…”

Section: Discussionmentioning

confidence: 99%

STING manifests self DNA-dependent inflammatory disease

Ahn

Gutman

Saijo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

444

393

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Inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and polyarthritis are characterized by chronic cytokine overproduction, suggesting that the stimulation of host innate immune responses, speculatively by persistent infection or self nucleic acids, plays a role in the manifestation of these disorders. Mice lacking DNase II die during embryonic development through comparable inflammatory disease because phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensor pathways are engaged, resulting in the production of a variety of cytokines including type I IFN. The cellular sensor pathway(s) responsible for triggering DNA-mediated inflammation aggravated autoimmune disease remains to be determined. However, we report here that Stimulator of IFN Genes (STING) is responsible for inflammation-related embryonic death in DNase II defective mice initiated by self DNA. DNase II-dependent embryonic lethality was rescued by loss of STING function, and polyarthritis completely prevented because cytosolic DNA failed to robustly trigger cytokine production through STING-controlled signaling pathways. Our data provides significant molecular insight into the causes of DNA-mediated inflammatory disorders and affords a target that could plausibly be therapeutically controlled to help prevent such diseases.

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Section: Discussionmentioning

confidence: 99%

STING manifests self DNA-dependent inflammatory disease

Ahn

Gutman

Saijo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

444

393

View full text Add to dashboard Cite

show abstract

“…It is pertinent to mention that LITAF binding sites have been identified on several promoters of pro-and anti-inflammatory mediators (MCP-1, IL-6, and IL-10) in addition to TNF, suggesting that the reduced LPS-induced lethality and milder clinical and histological inflammatory arthritis (IA) features observed in tamLITAF(i) −/− mice may result from the decrease of activation of mediators regulated by LITAF. Indeed, using anti-IL-6 and anti-IL-1 receptor mABs, Kawane et al (28) were able to impede the "cytokine storm" and block joint swelling. Furthermore, Maia et al (29) used ArthroMAB to induce CAIA, and found that removing the cytoplasmic domain of CD248 impaired TNF-α-induced monocyte adhesion, underscoring the importance of regulating TNF-α production in rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Merrill

You

Constable

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF −/− ) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i) −/− mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF −/− mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i) −/− mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i) −/− mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease-namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.septic shock | multiplex

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“…Our results indicate that NETs are internalized through an endocytic mechanism leading to lysosomal degradation, as shown by blockage of NET clearance by a mixture of endocytosis inhibitors, accumulation of extranuclear DNA on CQ treatment, and colocalization of these extranuclear DNA dots within Lamp-1 vesicles and lysosomes. DNase II resides in the lysosomal compartment and has been shown to digest DNA from apoptotic cells, and Nagata and coworkers have reported that its deficiency leads to activation of the innate immune system (25,35). Macrophages from DNase IIdeficient mice accumulate undigested DNA, resulting in the production of TNF-a and polyarthritis (28).…”

Section: Discussionmentioning

confidence: 99%

Macrophage Clearance of Neutrophil Extracellular Traps Is a Silent Process

Farrera

Fadeel

2013

The Journal of Immunology

348

292

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Neutrophil extracellular traps (NETs) facilitate the extracellular killing of pathogens. However, in recent years, excessive NET formation has been implicated in several pathological conditions. Indeed, NETs that are not removed from tissues or from the circulation might serve to trigger autoimmune responses. We observed that physiological amounts of DNase I do not suffice to completely degrade NETs in vitro, suggesting that additional mechanisms are required for the removal of these extracellular structures. We show in this article that human monocyte–derived macrophages are able to engulf NETs in a cytochalasin D–dependent manner, indicating that this is an active, endocytic process. Furthermore, preprocessing of NETs by DNase I facilitated their clearance by macrophages. In addition, both recombinant C1q and endogenous C1q derived from human serum were found to opsonize NETs, and this facilitated NET clearance. Upon internalization, NETs were apparently degraded in lysosomes, as treatment with chloroquine led to accumulation of extranuclear DNA in human monocyte–derived macrophages. Finally, uptake of NETs alone did not induce proinflammatory cytokine secretion, whereas LPS-induced production of IL-1β, IL-6, and TNF-α was promoted by the uptake of NETs. In summary, we show that macrophages are capable of clearance of NETs and that this occurs in an immunologically silent manner.

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Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

Cited by 97 publications

References 42 publications

STING manifests self DNA-dependent inflammatory disease

STING manifests self DNA-dependent inflammatory disease

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Macrophage Clearance of Neutrophil Extracellular Traps Is a Silent Process

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