Rheumatoid polyarthritis caused by a defect in DNA degradation

Macrophages phagocytose cells that die during programmed cell death and the nuclei that are expelled from erythroid precursor cells during erythropoiesis; subsequently, the ingested DNA is degraded in their lysosomes. A defect in this lysosomal DNA degradation activates the macrophages to produce cytokines such as IFNbeta and TNFalpha in a Toll-like receptor (TLR)-independent manner. IFNbeta thus produced in the mouse fetus induces the apoptosis of erythroid and lymphoid precursor cells, and kills the embryos. On the other hand, when the capacity for lysosomal DNA degradation is knocked out after birth, TNFalpha production increases in adulthood, causing chronic polyarthritis that resembles human rheumatoid arthritis. Here, I summarize recent findings on inflammatory diseases induced by such defects in DNA degradation.