Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

Abstract

Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

Caffeine Has Different Immunomodulatory Effect on the Cytokine Expression and NLRP3 Inflammasome Function in Various Human Macrophage Subpopulations

“…The NOD-like receptor (NLR) family belongs to the cytosolic PRRs, and plays a critical role in innate immunity through the recognition of a broad range of molecular patterns. Beside signal pathway regulation, many of the NLR family members (such as NLRP1, NLRP3, NLRC4) function as sensors in multiprotein complexes called inflammasomes that are responsible for the maturation process of IL-1β conductor cytokine [ 12 , 13 ]. The most studied inflammasome complex is the NLRP3 inflammasome that requires two signals for its function.…”

Peroxisome Proliferator-Activated Receptors (PPARs) and Oxidative Stress in Physiological Conditions and in Cancer

“…From PPARγ gene three different mRNA are transcribed (γ1, γ2, γ3) leading to the production of two proteins. All subtypes are involved in the regulation of lipid and carbohydrate metabolisms ( Table 1 ); moreover, based on their expression in specific cell types or tissues, PPARs can play a pivotal role in modulating different cell functions (proliferation, death, differentiation) [ 6 ], inflammatory process [ 7 ], angiogenesis [ 8 ], immune response [ 9 ].…”

Old and New Players of Inflammation and Their Relationship With Cancer Development

“…Independent on the source, immune and non-immune cells recognize PAMPs, DAMPs ( 1 ) and HAMPs through distinct receptors. PAMPs and DAMPs are recognized through membrane molecules known as pattern recognition receptors (PRRs), whereas HAMPs are sensed by nuclear receptors such as the thyroid hormone receptor, vitamin D receptor, estrogen receptor (ER), androgen receptor, glucocorticoid receptor, and PR, as well as adopted orphan receptors such as farnesoid X receptor (FXR), RAR-related orphan receptor (ROR), and PPARs ( 5 ).…”

“…PAMP and DAMP molecules bind to TLRs and NLR, stimulating the activation of several signaling pathways involved in a cascade of multi-protein complexes such as the inflammasome consisting of NLR, ASC adaptor protein, and pro-caspase 1 ( 10 ). Recent evidence suggests that the inflammasome component NOD-, LRR-, and pyrin domain-containing 3 (NLRP3), in addition to the direct interaction with PAMPs and DAMPs, also detect HAMPs, thereby modulating the inflammatory response ( 4 , 5 , 11 ).…”