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Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
Inflammasome is constitutive of the innate immune system and is responsible for regulating the immunological response to several stimuli. It consists mainly of a molecular pattern recognition receptor, an apoptosis-associated speck-like protein, which contains a caspase-recruitment domain adaptor protein, and a caspase-1 enzyme [19]. Recent reports identified single-nucleotide polymorphisms in the promoter and coding regions of NLR family pyrin domain containing 1 (Nlrp1) associated with vitiligo, vitiligo-associated autoimmune diseases, Addison disease, and type I diabetes [19]. Nlrp1 is highly expressed in T cells and Langerhans cells in the skin, explaining the potential role of mutant Nlrp1 in autoimmune diseases of the skin. This ultimately results in depigmentation in irregular patches of the skin and hair [19].
Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
The synthesis and secretion of pro-inflammatory cytokines are governed by germline-encoded receptors such as the TLRs and nucleotide-binding-domain and LRR-containing (NLR) proteins that can be activated by microbe- associated molecular patterns (MAMPs). For example, the production of active (mature) IL-1β and IL-18 occurs through a two-step process initiated by the transcriptional induction of a procytokine (e.g., a TLR stimulus) followed by caspase 1–mediated cleavage. In this process, NLRP3, also known as cryopyrin, associates with the NLR adaptor protein, apoptotic speck protein containing a CARD domain (ASC/PYCARD), to recruit procaspase 1. This complex is referred to as the inflammasome, and leads to the processing of procaspase 1 into active caspase 1. Caspase 1 is responsible for the subsequent cleavage of the IL-1β/IL-18 precursors into their functional forms. In addition to NLRP3, other NLRs, including NLRP1, NLRC4, and NAIP, also function in caspase-1 activation and IL-1β production through the formation of other inflammasomes in response to distinct sets of stimuli. Mice lacking NLRP3, ASC, or caspase 1 produce reduced levels of IL-1β and TNF-α and are protected from inflammation in acute, but not necessarily chronic, experimental colitis, suggesting that the NLRP inflammasome has a more critical role during the early phase of colitis.
Pathogenesis of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
Microglia perform several crucial functions in the brain including immune-surveillance for pathogens, cellular debris, apoptotic cells and neuronal phenotypic alterations. Upon activation microglia enter a primed position, and when stimulated in this state secrete increased amounts of inflammatory mediators, including IL-1β. As these specialized macrophages express pattern recognition receptors including TLR2 and TLR4, TLR ligation by DAMP (ATP, Hsp, HMGB1, etc.) strongly trigger microglia. Furthermore, several inflammasomes have been described in the microglia including NLRP1, NLRP3 and NLRC4. The NLRP3 inflammasome has been most often studied in the CNS, and is also the focus of the preponderance of studies in animal models of depression. Recent investigations also suggest that NLRP3 may be exquisitely sensitive to the homeostatic perturbations induced by psychobiological stress, with a mechanistic role for the inflammasome mediated processing and maturation of IL-1β in the generation of mood disorders.27 While space limitation does not allow a detailed description of animal studies highlighting the link between stress, DAMP and the NLRP3 inflammasome, it is clear that CNS inflammation caused by acute or chronic stress has an important role in the development of mood disorders.
Inflammasomes in placental explants of women with preeclampsia cultured with monosodium urate may be modulated by vitamin D
Published in Hypertension in Pregnancy, 2022
Priscila Rezeck Nunes, Mariana Romao-Veiga, Vanessa Rocha Ribeiro, Larissa Ragozo Cardoso de Oliveira, Igor de Carvalho Depra, Leandro Gustavo de Oliveira, Jose Carlos Peracoli, Maria Terezinha Serrao Peracoli
One of the most important PRRs is part of the family of NLR receptors (protein with nucleotide oligomerization domain), which are cytosolic proteins recognizing cytoplasmic damage-associated molecular patterns (DAMPs) and recruiting other proteins, forming signaling complexes that promote inflammation (7). The inflammasome is a large protein complex acting as a signaling receptor reacting to pathogen-associated molecular patterns (PAMPs) and DAMPs and mediates a highly inflammatory state, generating active forms of IL-1β and IL-18 (8), and releasing HMGB1 (high mobility group box-1) to the extracellular environment. This proinflammatory mediator contributes to the onset of the inflammatory response in PE (9,10). Three NLR proteins have been well studied: NLRP1, NLRP3, and NLRC4 (11).
Association between inflammasome-related polymorphisms and psoriatic arthritis
Published in Scandinavian Journal of Rheumatology, 2021
K Juneblad, A Kastbom, L Johansson, S Rantapää-Dahlqvist, P Söderkvist, G-M Alenius
To our knowledge, only one previous study has been published where SNPs in the inflammasome genes have been studied in patients with PsA (17). In that study, both rs2043211 in CARD8 and rs878329 in NLRP1 were analysed in comparison with population controls, although no significant associations were detected. There are several possible reasons underlying the differing results in our study compared to the previous Danish study. First, we studied different populations, with differences in background genetics, lifestyle exposures, and healthcare systems. Secondly, the previous study had a slightly smaller patient sample size (n = 459), and recruited PsA patients from the DANBIO registry, meaning that all patients were treated with at least csDMARDs, and many of them also bDMARDs. Our population was not selection biased for treatment, but instead represents a cross-sectional sample of PsA patients where 70% had ever been treated with csDMARDs.
An overview of disease models for NLRP3 inflammasome over-activation
Published in Expert Opinion on Drug Discovery, 2021
Hongliang Zhang, Ayesha Zahid, Hazrat Ismail, Yujie Tang, Tengchuan Jin, Jinhui Tao
The stimulus that activates NLRP3 inflammasome can often activate other inflammasomes, which share the same downstream products as NLRP3 inflammasome. NLRP3, NLRP1, NLRP6, NLRC4, and AIM2 can be activated by bacterial infections, NLRP3, AIM2, and NLRP9 can be activated by viral infection. NLRP3, NLRC4, and NLRP1 can be activated by sterile inflammation. NLRP3 and NLRP1 are simultaneously activated in AD and TBI [78,183], NLRP3, and NLRC4 are simultaneously activated in MS and SSc [184], while NLRP1, NLRP3, and AIM2 are simultaneously activated in LN [170] as depicted in Figure 1a. Therefore, it is important that during the evaluation of inhibitors, the state of the corresponding activated inflammasome must be tested in a specific model. Although inhibitors targeting other inflammasomes may benefit the disease treatment, side effects may also exist since diseases are complicated.