Negative regulation of ATP-induced inflammasome activation and cytokine secretion by acute-phase proteins: A mini review

Abstract

The expression of the acute-phase reactants C-reactive protein (CRP), α1-antitrypsin (AAT), and secretory leukocyte protease inhibitor (SLPI), is induced in response to inflammation by pro-inflammatory mediators, including interleukin-1β. It is conceivable that acute-phase proteins exert protective functions, when the integrity of an organism is challenged by pathogens or trauma, which result in uncontrolled release of endogenous damage-associated molecular patterns like Toll-like receptor agonists and ATP. Acute-phase proteins can enhance or down-modulate immunity against infections or protect the host against damage caused by over-shooting effector functions of the immune system. CRP is mainly regarded as a pro-inflammatory opsonizing agent that binds to bacteria and damaged host cells thereby contributing to their inactivation and elimination. AAT and SLPI are well known for their anti-protease activity, which protects the lung extracellular matrix against degradation by proteases that are released by activated neutrophil granulocytes. In addition, there is growing evidence, that CRP, AAT, and SLPI can control the biosynthesis, maturation, and secretion of pro-inflammatory cytokines. The purpose of this narrative mini review is to summarize these anti-inflammatory functions with a focus on the negative control of the ATP-induced, inflammasome-dependent secretion of interleukin-1β by monocytes. CRP-, AAT- and SLPI-mediated control of interleukin-1β release involves the activation of unconventional nicotinic acetylcholine receptors that inhibits the ionotropic function of the ATP receptor P2X7. Apart from other functions, CRP, AAT, and SLPI seem to be central elements of systemic negative feedback loops that protect the host against systemic hyperinflammation, barrier dysfunction, and death by multiple organ damage.

Activation of the microglial P2X7R/NLRP3 inflammasome mediates central sensitization in a mouse model of medication overuse headache

“…It has been demonstrated in earlier studies that the NLRP3 inflammasome, which is downstream of P2X7R, is implicated in the pathophysiology of a variety of disorders ( Territo and Zarrinmayeh, 2021 ; Li et al, 2022 ; Richter et al, 2022 ). Thus, we further investigated the changes in the NLRP3 inflammasome after repeated SUMA injection in this study.…”

Reframing the link between metabolism and NLRP3 inflammasome: therapeutic opportunities

“…It is currently accepted that cellular stress induced by these stimuli trigger the activation of NLRP3 inflammasome through K + or Clefflux, Ca 2+ flux, lysosomal disruption, mitochondrial dysfunction and reactive oxygen species (ROS) generation, metabolic signals and trans-Golgi disassembly (79-81), and it seems that K + efflux is the convergence point for the activation of NLRP3 inflammasome (82)(83)(84). However, other levels of regulation have been described such as epigenetic regulation by microRNAs (85,86), subcellular localization (87), crosstalk between the gut microbiota and NLRP3 is involved in signaling in the gut-brain axis (88), exosomes (89), acute-phase proteins (90) or neuropeptide Calcitonin Gene-Related Peptide (CGRP) (91).…”

Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems

“…However, if we accept that the host will reprogram its metabolism to try and get rid of the virus [ 43 ], which is likely linked to more general systemic effects related to the inflammatory-driven acute phase response (APR) and insulin resistance and alterations in lipid metabolism [ 113 ], then the boundary between “directly virus induced” vs. “host response to virus” becomes less clear. This definition becomes even more blurred with evidence that some proteins released during the APR can actually suppress inflammasome activation, hinting at the host trying to suppress excessive inflammation [ 114 ]. The metabolic link is perhaps further strengthened as COVID-19 not only worsens existing diabetes but can trigger it in people who did not previously have it; although some of the mechanisms mentioned above could be important, there is also some evidence of direct damage to the pancreas [ 115 ].…”