Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

Abstract

SUMMARY Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular micro-particle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanismcan contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.

Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells

“…Perhaps cavity dwelling macrophages can be recruited to dying cells in their cavities as well as neighboring organs. As cavity resident cells these macrophage populations may also have limited exposure to circulating proteins, such as DNASE1L3, which digests DNA in microparticles released from ACs (Sisirak et al, 2016), One interesting possibility is that cavity resident macrophages utilize additional mechanisms to limit responses to ACs because of reduced DNase activity in these compartments.…”

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis

“…Bone marrow-derived DCs exposed to acetylated nucleosomes undergo maturation and activate syngenic T cells. Apoptotic microparticles, which expose modified nucleosomes at the cell surface (123-125), are found in both SLE patients and mice (125-127). Apoptotic microparticles from MRL/ lpr mice express elevated levels of modified chromatin and induce enhanced maturation of DCs than BALB/c mice (125).…”

“…Apoptotic microparticles from MRL/ lpr mice express elevated levels of modified chromatin and induce enhanced maturation of DCs than BALB/c mice (125). DNASE1L3 is a serum enzyme that is critical for the degradation of chromatin in microparticles precluding autoantibody recognition of microparticle DNA and humans and mice lacking DNASE1L3 develop SLE-like disease (127-131). Microparticles from SLE patients express apoptosis-related histone modifications while these were absent in microparticles from healthy individuals (126).…”

The many ways tissue phagocytes respond to dying cells

“…DNASE1L3, a circulating DNase produced primarily by macrophages and DC, digests the genomic DNA in apoptotic cell derived membrane-bound vesicles called microparticles (246). These microparticles are smaller than apoptotic bodies and can be found in the plasma of SLE patients bound to IgG to form a type of immune complex that may contribute to pathogenesis (247, 248).…”

“…These microparticles are smaller than apoptotic bodies and can be found in the plasma of SLE patients bound to IgG to form a type of immune complex that may contribute to pathogenesis (247, 248). A highly basic C-terminal peptide in DNASE1L3 enables its association with liposomes encapsulating DNA (249), and this property of DNASE1L3 is thought to enable its digestion of surface-exposed chromatin exposed on microparticles thereby preventing autoantibody binding (246, 250). Dnase1l3 -deficient mice develop antibodies to dsDNA and chromatin and exhibit features of SLE including glomerulonephritis (246).…”