The NLR (nucleotide-binding domain leucine-rich repeat containing) family is found in plants and animals, and serves as crucial regulators of inflammatory and innate immune response, though its functions are likely to extend greatly beyond innate immunity, and even beyond the immune system. This review discusses recent findings regarding the function of NLR proteins in the control of IL-1, NF-kappaB, and host response to pathogens including distinct forms of cell death. The review also covers recent advances regarding the biochemical nature of NLRs, its regulation by intracellular nucleotides and extracellular ATP, by the chaperone protein HSP90, and the ubiquitin ligase-associated protein SGT1. Its role in inflammation is linked to the formation of biochemical complexes such as the inflammasome, and its roles in cell death might be linked to the proposed formation of pyroptosome and necrosome.
"How the opposing immunological phenotypes in cancer are controlled is not well known, but nod-like receptors (NLRs) have been implicated in various stages of the disease process and have the required capacity to act as key regulators of physiological and pathological inflammation (7–9). NLRs are initiators of the inflammasome pathway, a cytosolic signaling apparatus that canonically activates caspase-1, and IL-1β and IL-18 thereafter (10). NLRs can respond to both pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively), and the pathway has been shown to have important roles in mounting immune responses to both microbial pathogens and damaged self, as well as regulating tissue repair after damage (11, 12). "
[Show abstract][Hide abstract] ABSTRACT: It is believed the immune system can contribute to oncogenic transformation especially in settings of chronic inflammation, be activated during immunosurveillance to destroy early neoplastic cells before they undergo malignant outgrowth, and finally, can assist growth of established tumors by preventing clearance, remodeling surrounding tissue, and promoting metastatic events. These seemingly opposing roles of the immune system at the different stages of cancer development must all be mediated by innate signaling mechanisms that regulate the overall state of immune activation. Recently, the cytosolic nod-like receptor (NLR) pathway of innate immunity has gained a lot of attention in the tumor immunology field due to its known involvement in promoting inflammation and immunity, and conversely, in regulating tissue repair processes. In this review, we present all the current evidence for NLR involvement in the different stages of neoplasia to understand how a single molecular pathway can contribute to conflicting immunological interactions with cancer.
Frontiers in Immunology 04/2014; 5:185. DOI:10.3389/fimmu.2014.00185
"Cryopyrin (NALP3 protein), which is mutated in CAPS, plays a central role in the recognition of danger signals and the ensuing immunological cascade . Cryopyrin is a family member of the intracellular 'NOD-like' receptors (NLRs) [Ye and Ting, 2008]. NLRs aggregate to a multiprotein complex, the so-called inflammasome, which, after activation , leads to caspase-1-induced IL-1β secretion [Petrilli et al. 2007]. "
[Show abstract][Hide abstract] ABSTRACT: The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1-2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.
Therapeutic advances in musculoskeletal disease 12/2013; 5(6):315-329. DOI:10.1177/1759720X13502629
"NLR proteins are characterized by the presence of three homologous domains: a central nucleotide-binding and oligomerization (NACHT) domain, a C-terminal leucine-rich repeat domain (LRR), and an N-terminal effector domain (18, 19). As the name indicates, the NACHT domain is important for oligomerization, the LRR domain is important for ligand sensing, and the N-terminal effector domain recruits downstream signaling molecules (20, 21). "
[Show abstract][Hide abstract] ABSTRACT: Inflammation plays a critical role in tumorigenesis and can contribute to oncogenic mutations, tumor promotion, and angiogenesis. Tumor-promoting inflammation is driven by many factors including the presence of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. One major source of IL-1β and IL-18 secretion is through the activation of inflammasomes. Inflammasomes are multi-protein complexes that upon activation lead to the processing and secretion of IL-1β and IL-18 mediated by the cysteine protease caspase-1. Several inflammasomes, including NLRP3, NLRC4, and NLRP6, have been implicated in tumorigenesis. However, inflammasomes play divergent roles in different types of cancer reflecting the complexity of inflammation during tumorigenesis. Understanding the role of inflammasome activation during specific stages of tumorigenesis and also during cancer immunotherapy will help identify novel therapeutic targets that could improve treatment strategies for cancer patients. Here we will discuss recent advances in understanding the mechanism by which NLRs regulate carcinogenesis.
Frontiers in Immunology 11/2013; 4:370. DOI:10.3389/fimmu.2013.00370
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