Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

• Published in: The Journal of clinical investigation 2017-06, Vol.127 (6), p.2022-2029
• Main Authors: Weigt, S Samuel, Palchevskiy, Vyacheslav, Belperio, John A
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Apoptosis; Biology; Biomedical research; Caspase; Caspase-1; Cell activation; Chemokines; Cytokines; Enzymes; Graft rejection; Graft Rejection - immunology; Graft Rejection - metabolism; Health aspects; Humans; Immunity, Innate; Inflammasomes; Inflammasomes - physiology; Inflammation; Interleukin 1; Interleukin-1 - physiology; Interleukins; Ischemia; Ligands; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Neutrophils; Pathogenesis; Pathogens; Physiological aspects; Primary Graft Dysfunction - immunology; Primary Graft Dysfunction - metabolism; Proteins; Pyroptosis; Reperfusion; Review; Rodents; Sensors; Transplants & implants; Trauma; Uric acid
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI93537

Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern-recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen-associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro-IL-1β. This is followed by signal two, which involves recognition of PAMPs or damage-associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase-1-dependent cleavage of pro-IL-1β to active IL-1β and pyroptosis. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL-1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction.