Abstract
Overactive inflammatory responses are central to the pathophysiology of many hemolytic
conditions including sickle cell disease. Excessive hemolysis leads to elevated serum
levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme
has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1
and release of pro-inflammatory cytokines IL-1β and IL-18. Heme also activates the
non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation
and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies
indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients
with sickle cell disease and other hemolytic conditions. However, a thorough understanding
of the mechanisms of heme-induced inflammasome activation is needed to fully leverage
this pathway for clinical benefit. This review will explore the mechanisms of heme-induced
NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions
including sickle cell disease.
Abbreviations:
ASC (apoptosis-associated speck-like protein containing a CARD), CARD (caspase activation and recruitment domain), DAMP (damage associated molecular pattern), GSDMD (gasdermin D), Hb (hemoglobin), HO-1 (heme oxygenase-1), Hp (haptoglobin), Hpx (hemopexin), IL (interleukin), MD-2 (myeloid differentiation factor-2), Mb (myoglobin), MLKL (mixed lineage kinase domain like pseudokinase), mtROS (mitochondrial reactive oxygen species), NET (neutrophil extracellular trap), NLRP3 (nod-like receptor protein with a PYRIN domain 3), NOX2 (NADPH oxidase-2), PAMP (pathogen associated molecular pattern), PI3K (phosphoinositide 3-kinase), PRR (pattern recognition receptor), SCD (sickle cell disease), Syk (spleen tyrosine kinase), TLR (toll-like receptor), TNFα (tumor necrosis factor alpha), TNFR1 (tumor necrosis factor receptor 1), VCAM-1 (vascular cell adhesion molecule 1)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: August 27, 2022
Accepted:
August 21,
2022
Received in revised form:
July 29,
2022
Received:
June 14,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
