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  • This study is intriguing for several reasons For

    2021-09-15

    This study is intriguing for several reasons. For acute pancreatitis and acute hepatitis, the early impact of inflammatory cell activation has recently been highlighted and macrophages seem to play a critical role in the disease initiation and severity., , To activate the NLRP3 inflammasome, a 2-checkpoint model of priming and activation has been proposed in which TLR-4 (or TLR-9) represent the second checkpoint. Although the role of TLRs in bacterial infection is unequivocal, research continues on its importance for sterile inflammation, such as the early phase of pancreatitis., , The net effect of NLRP3 inflammasome activation is the proteolytic cleavage and activation of the strongly pro-inflammatory cytokine IL-1β, which regulates most of the systemic inflammatory response syndrome. Constitutive overexpression of IL-1β in the pancreas alone was found to be sufficient to induce spontaneous pancreatitis. Reducing the action of the NLRP3 inflammasome would therefore be expected to have a beneficial effect on either the onset or the severity of the disease. Inflammasomes assemble to key signaling platforms that detect pathogenic microorganisms and sterile stressors before leading to downstream activation of IL-1β. The 2-step model of priming and activation of the canonical NLRP3 inflammasome predicts that the basal Malonic acid receptor of its components is insufficient for its activation in resting cells. An initial activating signal transmitted via pattern recognition receptor on the cell surface results in up-regulation of the NLRP3 components and represents the priming reaction. Only thereafter can the NLRP3 inflammasome be activated via LPS stimulation of its receptor, the TLR-4, which then induces activation of TRIF, the binding of NLRP3 to ASC, and the subsequent caspase 1–dependent induction of pro–IL-β1 expression and its activation. Although LPS-stimulated TLR-4 activation is probably the best investigated mechanisms of NLRP3 inflammasome activation, other mechanisms involving bacterial membrane components, the release of cathepsin B from lysosomes, low potassium levels, high intracellular calcium concentrations, or the release of reactive oxygen species from mitochondria have all been implicated in this process (). Lactate has long been regarded as critical for energy (ATP) generation when oxygen is in short supply (anaerobic glycolysis) and rising levels in the blood were regarded as an early sign of microcirculatory failure. It was only recently discovered that lactate is also a signaling molecule and a ligand for a dedicated lactate receptor. The GPR81 is a 7-transmembrane receptor Malonic acid receptor and binding of lactate leads to recruitment of the intracellular adaptor ARRB2 before downstream signaling is transmitted. From Hoque et al, we learn that this signal ultimately reduces the activation of the NLRP3 inflammasome, with all its beneficial effects on macrophages/monocytes and 2 experimental inflammatory diseases of the liver and pancreas. The exact mechanism through which GPR81 and ARRB2 counteract the NLRP3 and TLR pathways is currently unknown () and will require further study. Lactate possesses several chemical and metabolic effects outside this signaling cascade and these include a reduction in pH. A lower pH, on the other hand, could have several unwanted consequences as far as the pancreas is concerned: The pancreatic acinar cell stores its proteases in acidic secretory vesicles and when pancreatitis is induced the pH in intracellular compartment becomes more acidic and a premature protease activation begins. For this premature intracellular protease activation, 2 mechanisms have been proposed and involve trypsinogen activation by cathepsin B or trypsinogen autoactivation, both of which are pH dependent., Chloroquine, an agent that raises the intracellular pH, reduces premature zymogen activation and ameliorates the course of experimental pancreatitis. A proton pump, the vacuolar ATPase, regulates zymogen activation in the acinar cell and an acid challenge sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury. All of these observations would suggest that lactate, at concentrations that reduce pH or lead to supraphysiologic lactate concentrations, would have a negative effect on the disease onset or severity. However, the experimental concentrations used by Hoque et al would only result in lactate levels of 0.3 mmol/L, which are well within the physiologic range and therefore unlikely to affect pH or have pathologic effects.