Abstract
Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.
Highlights
Inflammation is a biological process through which the body’s innate immune system counters the invading pathogens and senses cellular signals generated during a pathogenic invasion [1,2]
The cardinal feature of the triggering step is the activation of inflammasomes, intracellular multiprotein complexes consisting of intracellular pattern recognition receptors (PRRs), such as nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene-I-like receptors (RLRs), absent in melanoma 2 (AIM2), AIM2-like receptors (ALRs), caspase-11, caspase-4, and various inflammatory molecules, such as ASC, caspase-1, and lipopolysaccharide (LPS) [11,12]
Inflammasome activation induces the proteolytic activation of caspase-1, which induces the proteolytic activation of gasdermin D (GSDMD) and N-terminal fragments of GSDMD (N-GSDMD)-mediated pyroptosis via the formation of membrane pores [11,12,13,14,15]
Summary
Inflammation is a biological process through which the body’s innate immune system counters the invading pathogens and senses cellular signals generated during a pathogenic invasion [1,2]. Non-canonical inflammasomes, mouse caspase-11 and human caspase4/5, were recently identified and have been demonstrated to be activated in response to a unique ligand, LPS [20,21,22]. Growing evidence has indicated that flavonoids affect inflammatory diseases by targeting inflammasome activation, the main feature of the triggering step [32,33,34,35]. Many of the rheumatic diseases are considered autoimmune and inflammatory disorders, but not all rheumatic diseases are related to autoimmune and inflammatory conditions [36,37] This is a narrative review that aims to discuss the studies investigating the pharmacological effects on rheumatic diseases of flavonoids (Table 1) targeting inflammasome activation, and to provide new insights into the development of flavonoids as potential nutraceuticals to prevent and treat inflammatory and autoimmune diseases, including rheumatic diseases
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