The grateful dead: damage‐associated molecular pattern molecules and reduction/oxidation regulate immunity

Abstract

The response to pathogens and damage in plants and animals involves a series of carefully orchestrated, highly evolved, molecular mechanisms resulting in pathogen resistance and wound healing. In metazoans, damage- or pathogen-associated molecular pattern molecules (DAMPs, PAMPs) execute precise intracellular tasks and are also able to exert disparate functions when released into the extracellular space. The emergent consequence for both inflammation and wound healing of the abnormal extracellular persistence of these factors may underlie many clinical disorders. DAMPs/PAMPs are recognized by hereditable receptors including the Toll-like receptors, the NOD1-like receptors and retinoic-acid-inducible gene I-like receptors, as well as the receptor for advanced glycation end products. These host molecules 'sense' not only pathogens but also misfolded/glycated proteins or exposed hydrophobic portions of molecules, activating intracellular cascades that lead to an inflammatory response. Equally important are means to not only respond to these molecules but also to eradicate them. We have speculated that their destruction through oxidative mechanisms normally exerted by myeloid cells, such as neutrophils and eosinophils, or their persistence in the setting of pathologic extracellular reducing environments, maintained by exuberant necrotic cell death and/or oxidoreductases, represent important molecular means enabling chronic inflammatory states.

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

“…In this regard, the intestinal surface is under continual renewal with rapid epithelial turnover in the steady state, and lymph-borne DCs have been shown to contain cytoplasmic apoptotic DNA, epithelial cell-restricted cytokeratins, and epithelial cell-associated nonspecific esterase + inclusions-indicative of a continuous transport of apoptotic intestinal epithelial cell remnants to the MLN (43). As it more recently has become clear that intestinal epithelial cell death also can occur through necroptosis (45), a process associated with the release of a wide range of DAMPs including IL-1 cytokine family members (46), and because a number of DAMPs bind to receptors utilizing MyD88 as a signaling adaptor (47), it remains possible that this pathway plays a role in promoting steady-state migration of SI LP CD103 + DCs to the MLN. In this context, it would also be interesting to examine the impact of simultaneous genetic deficiency in IL-1b, IL-18, and IL-33.…”

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

“…[3][4][5][6][7] High-mobility group box protein 1 (HMGB1), originally identified as a DNA-binding protein, is a proximal trigger that is sufficient to induce the release of other cytokines classically associated with mediating inflammatory responses, including tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and interleukin-6 (IL-6). 8 Interestingly, HMGB1 was rapidly mobilized and released into system circulation by hepatocytes in the setting of liver I/R injury. 8,9 HMGB1 has also been reported to participate in ALI and lung inflammatory response induced by endotoxin, ventilator, and hemorrhage.…”

“…8 Interestingly, HMGB1 was rapidly mobilized and released into system circulation by hepatocytes in the setting of liver I/R injury. 8,9 HMGB1 has also been reported to participate in ALI and lung inflammatory response induced by endotoxin, ventilator, and hemorrhage. [10][11][12] For example, HMGB1 expression in the lung was found to be increased within 4 h of hemorrhage, and then remained elevated for more than 72 h after blood loss.…”

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

“…Cell damage in noninfectious tissue injury activates an 'injury identification' stage through the production of molecular markers released as damage-associated molecular pattern molecules. 2 These actions aim to isolate and repress pathogens and the damage, but normal cells within the environment are also unavoidably damaged. The ambient tissue (redox state) and the balance between opposing proinflammatory mediator concentrations will determine whether inflammation or tissue protection dominates.…”