Abstract
Inflammation is a body’s protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps—a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of ‘canonical’ inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as ‘non-canonical’ inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.
Highlights
Inflammation is a series of innate immune responses to protect the body from various invading pathogens and cellular danger stress signals [1,2]
The same studies suggest that extracellular LPS derived from Gram-negative bacteria is internalized in several ways, including MD2/CD14/TLR4-mediated endocytosis, outer membrane vesicles (OMVs) formation, and high-mobility group box 1 (HMGB1)/receptor for advanced glycation end-product (RAGE)-mediated endocytosis, and the internalized LPS in endosomes is exposed with help from Guanylate-binding proteins (GBPs) to cytosolic caspase-11 to induce caspase-11 non-canonical inflammasome-activated inflammatory responses
Selective and effective targeting of caspase-11 non-canonical inflammasome by downregulating its expression via its specific small interfering RNA or CRISPR/Cas9 technology could be a promising strategy to treat infectious and inflammatory diseases, including rheumatoid arthritis, infectious diseases caused by Gram-negative bacteria, such as Citrobacter rodentium, Salmonella typhimurium, Burkholderia thailandensis, and Legionella pneumophila, neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease, inflammatory bowel diseases, such as colitis, and inflammatory respiratory disease, such as chronic obstructive pulmonary disease since caspase-11 non-canonical inflammasome plays a critical role in inducing inflammatory responses in these infectious and inflammatory diseases [14]
Summary
Inflammation is a series of innate immune responses to protect the body from various invading pathogens and cellular danger stress signals [1,2]. The triggering step, on the other hand, is initiated by the interaction of intracellular PRRs, such as the nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene-I-like receptors, absent in melanoma 2, absent in melanoma 2-like receptors, caspase-11, and caspase-4 with a variety of PAMPs and DAMPs [11,12] This interaction subsequently forms an inflammatory protein complex (inflammasome) and induces the caspase-1-mediated proteolytic maturation of pro-inflammatory cytokines, IL-1β and IL-18 as well as the gasdermin D (GSDMD)-mediated formation of membrane pores and pyroptosis (an inflammatory form of cell death) [11,12,13,14]. This review highlights the promising strategy for developing novel therapeutics for the prevention and treatment of infectious and inflammatory diseases by selectively targeting caspase-11 non-canonical inflammasome
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