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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.
The gastrointestinal tract
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
A rare, and often lethal, form of enterocolitis in infancy has been described. Early reports suggested autosomal recessive inheritance, but more recently it has been associated with heterozygous pathogenic variants in NLRC4. The condition is called autoinflammation with infantile enterocolitis (AIFEC). It presents with failure to thrive, gastrointestinal symptoms and febrile episodes.
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.
Latent Upregulation of Nlrp3, Nlrc4 and Aim2 Differentiates between Asymptomatic and Symptomatic Trichomonas vaginalis Infection
Published in Immunological Investigations, 2022
Sonal Yadav, Vivek Verma, Rakesh Singh Dhanda, Sumeeta Khurana, Manisha Yadav
NLRC4, also called IPAF, CLAN, and card12; it regulates activation of caspase-1 and IL-1β. Its response is not directly mediated. NAIPs; first, interact with the type III secretion system (T3SS) components like rods and needle and flagellin proteins and then interact with NLRC4 and causing its oligomerization (Hafner-Bratkovič 2017; Paintlia et al. 2002). Tumor necrosis factor-alpha (TNFα), p53, and exposure to UV radiation can directly induce transcription of Ipaf in some human cells compared to un-stimulated cells (Gutierrez et al. 2004; Paintlia et al. 2002; Sutterwala and Flavell 2009). In bacterial infection, NLRC4 leads to IL-1β expression through caspase-1. S. enteric, L. pneumophila, L. monocytogenes activated the NLRC4 pathway and resulted in infection clearance (Skeldon and Saleh 2011). During fungal infection, Tomalka et al. found that NLRC4 played a role in limiting the growth of candida in the mucosal stroma (Tomalka et al. 2011). Sadasivam et al. reported an increased immune-reactivity for p53 in T. vaginalis infected women (Sadasivam et al. 2005). A study reported increased levels of TNF-α in the vaginal–cervical lymphocytes of BALB/c mice infected with T. vaginalis isolates obtained from asymptomatic women as compared to isolates of symptomatic women (Paintlia et al. 2002).
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).
Macrophage activation syndrome in systemic juvenile idiopathic arthritis
Published in Immunological Medicine, 2021
Moreover, recent studies have revealed a close association between IL-18 and the development of MAS [45]. Canna et al. have identified a new monogenic autoinflammatory disease associated with gain-of-function mutations of the NLRC4 gene, an inflammasome sensor that causes a disease characterized by early-onset, recurrent MAS [45]. Mutations of NLRC4 cause and trigger constitutive caspase-1 cleavage and increased production of IL-18 [45]. The most characteristic immunological finding was extremely high IL-18 levels equal to those in patients with MAS and s-JIA, providing evidence that NLRC4 is particularly important in regulating IL-18 production and in further supporting the role of IL-18 as a predisposing factor for MAS. These findings indicate that IL-18 is another mediator in s-JIA and that its overproduction may be closely related to the development of MAS.