Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

Abstract

High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death.

Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin-1 beta production in peripheral blood mononuclear cell

“…Upon its activation by innate receptors such as Toll and NOD like receptors (TLRs and NLRs respectively), the inflammatory response is initiated and sustained, for as long as the triggering agent is present. The inflammation in SCA is proposed to be dependent on TLR and NLR signaling since erythrocyte could be recognized as DAMPs [7,19,34,55,56].…”

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

“…In in vivo systems, these effects can be difficult to study, as histones are co‐released with nuclear DNA and other nuclear DAMPs such as HMGB1 (high mobility group box protein 1), each with their individual activities. Indeed, the mechanism of cell necrosis has significant impact on the kinetics of nuclear DAMP release,11 and nuclear DAMPs acting as complexes have been reported to exert different activities compared to protein isolates 12. Furthermore, where purified histones injected into experimental animals are lethal within minutes,13 necrotic cell death releases nucleosomes (ie: histone‐DNA complexes) which overall appear to be less toxic 14.…”

“…Indeed, the mechanism of cell necrosis has significant impact on the kinetics of nuclear DAMP release, 11 and nuclear DAMPs acting as complexes have been reported to exert different activities compared to protein isolates. 12 Furthermore, where purified histones injected into experimental animals are lethal within minutes, 13 necrotic cell death releases nucleosomes (ie: histone-DNA complexes) which overall appear to be less toxic. 14 Indeed a study injecting similar doses of nucleosomes in mice makes no mention of toxicity, 15 and others have demonstrated cofactors such as HMGB1 responsible for the immune-stimulatory effects of nucleosomes.…”

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

“…Among other receptors, HMGB1 binds to TLRs and RAGE, both of which are implicated in liver disease [100,101]. HMGB1 is secreted in response to tissue injury or local and systemic inflammatory responses [102] and drives the profibrogenic response to liver injury [103,104]. Thus, it has been proposed that, during fibrogenesis, hepatocytes and KC increase and secrete [105] HMGB1 that acts either as an autocrine signal targeting themselves, creating a feedback loop, or as a paracrine signal targeting hepatic stellate cells.…”