Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages

Abstract

A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.

Type I interferonopathies—an expanding disease spectrum of immunodysregulation

“…This is achieved by confinement of certain nucleic acid species to distinct cellular compartments away from the cytosolic nucleic acid sensing machinery [4]. In addition, clearance of DNA derived from cell debris is accomplished by nucleolytic DNA degradation within the extracellular space or following phagocytosis within the lysosome [16,17]. Finally, pattern recognition is also determined by structural properties or chemical modification of nucleic acid ligands as outlined above.…”

Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players

“…DNase II is an intracellular nuclease present in phagocytic cells necessary to degrade phagocytosed chromatin. In DNase II knock out mice undigested DNA in lysosomes leaks into the cytoplasm and causes the production of lethal amounts of IFN-I [155]. Summarizing, SNEC-IC may be considered binary pyrogens which induce much more inflammation than its single components separately.…”

Pullulan-histone antibody nanoconjugates for the removal of chromatin fragments from systemic circulation

“…Histones and non-degraded DNA accumulated in macrophages leads to the production of high levels of type 1 interferons (IFN) [49]. Accumulation of non-degraded DNA in macrophages is reported to induce the production of inflammatory cytokines including IFN and TNF-a [50]. Thus reduction in the inflammatory cytokines can be attributed to the removal of the chromatins from the systemic circulation by the nanoconjugates.…”