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Airway Epithelial and Early Innate Immune Responses toVirus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Alan Chen-Yu Hsu, Su-Ling Loo, Faezeh Fathi Aghdam, Kristy Parsons, Philip M. Hansbro, Peter A. B. Wark
NLRs (Figure 3.3) are the third set of PRRs that recognize viral RNAs during infection. NLR protein (NLRP) 3 recognizes viral dsRNA/ssRNAs and then binds to apoptotic speck protein containing caspase activation and recruitment domain (AC), forming a complex known as the NLRP3 inflammasome. This complex then cleaves pro-caspase 1 into a functional caspase 1, which in turn cleaves pro-interleukin (IL)-1 into its active form, IL-1β. The released IL-1β protein then binds to toll/IL-1 receptors on the same or neighboring cells, and induces the expression of inflammatory cytokines via NF-κB activation.26 Another function of IL-1β is to recruit neutrophils and further increase inflammation in the airways.27–29 Viral infections, including influenza and RV, can also upregulate the protein induction of NLRP3, forming a positive feedback loop that reinforces inflammatory responses.27,30
The immune response to fungal challenge
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Jeffery Hu, Jeffery J. Auletta
Additional PRRs relevant to fungal pathogens include C-type lectin receptors (CLR) [20], including β-glucan (Dectin-1) [21,22] and mannose receptors (MRs) [23], and complement receptors (CRs). Like TLRs, these PRRs are located on the surface of phagocytes, including macrophages, DCs, and neutrophils, and can modulate immune cell function [24]. Dectin 1 (also known as CLEC7A) is the most well-studied CLR expressed on monocytes and macrophages. Ligation of Dectin-1 and MRs initiates phagocytosis in the absence of opsonization (see sections on phagocytosis and complement below), whereas dual ligation of complement receptors, like CR3 (CD11b/CD18 or Mac-1), with receptors for the Fc portion of immunoglobulins (FcRs) dramatically enhance microbial phagocytosis [25]. Additionally, dectin-1 is involved in inducing cytokine production and amplification of response from TLR2 or TLR4 pathway [26,27]. Dectin-1 accomplishes this task via two intracellular signaling: the spleen tyrosine kinase (SYK), caspase activation and recruitment domain containing 9 (CARD9), and protein kinase Cδ pathway [28–32] and the RAF1 kinase signaling pathway [33]. Polymorphisms in the Dectin 1 gene are associated with colonization of the genitourinary tract by Candida species, recurrent vulvovaginal candidiasis, and other fungal infection [34–37] whereas CARD9 deficiency showed more severe phenotype demonstrating increased susceptibility to invasive candidiasis [31]. While many other PRRs exist such as NOD-like receptors (NLR), the overall goal of PRRs serves to initially detect infection and coordinate the appropriate response through crosstalk and synergism between PRR and their downstream adaptor protein.
Phagocytic cells and their functions
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, John W. Sleasman
One of the most biologically important consequences of phagocytosis is the release of pro-inflammatory cytokines. In the case of ingestion of opsonized particles, the engagement of Fcγ receptors and C3b receptors triggers the activation cascade that leads to the release of cytokines, proteases, oxygen radicals, and other proinflammatory compounds. However, such activation can also be induced as a consequence of innate immunity reactions involving the recognition of pathogen-associated molecular patterns (PAMPs) or endogenous danger-associated molecular patterns (DAMPs) by pattern-recognition receptors (PRRs). The activation of PPRs results in a cascade of events including the assembly of multimolecular complexes known as inflammasomes, which recruit inactive pro-caspase-1 proteins that oligomerize and are autoproteolytically cleaved into caspase-1. Activated caspase-1 cleaves the inactive precursors of IL-1 and IL-18 that are consequently released in their active forms. One of the main components of the inflammasome are nod-like receptor proteins (NLRPs), particularly NLRP3 and NLRC4. Functionally, NLRs are sensors required for the formation of the inflammasome and recognize a variety of cellular damage or cellular infection products including DAMPs and PAMPs. Structurally, NLRPs contain a pyrin domain, while NLRC contain a caspase activation and recruitment domain (CARD). There is a major difference between those inflammasomes. NLRP3, after priming as a consequence of the binding of LPS to TLR4, can be activated by a wide variety of stimuli, such as reactive oxygen species, mitochondrial DNA, cardiolipin, or the release of cathepsins. NLRC4 (NLR family CARD domain-containing protein 4) needs to oligomerize with NAIP (NLR family apoptosis inhibitory protein) forming a NAIP/NLCR4 inflammasome that contains ASC (Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD) required for maximal inflammasome activation. Dying cells release ASC that can be taken up by other cells, propagating its proinflammatory activity from cell to cell. Probably a consequence of these properties, the NAIP/NLCR4 inflammasome has been identified as a cause of spontaneous autoinflammatory disorders.
Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of “Immune TOR-Opathies”
Published in Fetal and Pediatric Pathology, 2023
Mai He, Amanda Wong, Kimberly Sutton, Mercia Jeanne Bezerra Gondim, Charles Samson
Caspase activation and recruitment domain 11 (CARD11) is an adaptor protein in lymphocytes that facilitates signal transduction downstream of T cell or B cell receptor activation to initiate activation of NF-κB and other signaling pathways through forming a scaffold called CBM (CARD11-BCL10-MALT1) signalsome complex [18]. Multiple different types of variants for CARD11 have been described, each of which leads to the development of different clinical phenotypes [19,20]. To validate novel gene variants for pathogenicity, functional assays could be performed utilizing a CARD-11 deficient Jurkat T cell line expressing an NF-κB GFP reporter [19]. Mutations affecting the CARD11-BCL10-MALT1 (cbm) signalosome complex are associated with an abnormal activation of the mtor/s6k signaling pathway [6]. It is true that this variant may be novel as a cause of VEO-IBD, although in a study of severe atopic disease due to different CARD11 mutations, 3 of 8 patients had GI manifestations including eosinophilic proctocolitis in an 18 month old (other two patients were teenagers with ulcerative colitis and chronic diarrhea, respectively) [21]. Another study suggested that the CARD family, including CARD11, was likely to be involved in inflammatory bowel disease [22].
Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Tiantian Fan, Yinchun Ji, Danqi Chen, Xia Peng, Jing Ai, Bing Xiong
Receptor-interacting protein kinase 2 (RIPK2) belongs to RIPK family which consists of seven protein kinases that share homology in the serine-threonine kinase domain1. In addition to the kinase domain, each member has its unique domain structure enabling it to interact with proteins to execute specific cellular signalling processes1. In RIPK2, it contains a carboxy-terminal caspase activation and recruitment domain (CARD), which facilitates homotypic interactions with other CARD-containing proteins, especially the pattern recognition receptor nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2)2,3. These structure characteristics, together with biochemical studies, positioned RIPK2 as an essential protein kinase with the capacity to regulate immune signalling, triggering more researches and drug development on targeting RIPK2.
Emerging therapeutic targets and preclinical models for severe asthma
Published in Expert Opinion on Therapeutic Targets, 2020
Izabela Galvão, Richard Y. Kim, Sijie Shen, Kurtis F. Budden, Angélica T. Vieira, Philip M. Hansbro
Inflammasomes are multi-protein complexes that mediate robust innate immune responses following exposure to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). They are comprised of a pattern recognition receptor (PRR), the adaptor protein apoptosis-associated speck-like protein containing caspase activation and recruitment domain (CARD; ASC), and the effector protein, caspase 1, which is responsible for the recruitment, maturation, and release of IL-1β. The nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein (NLR) family of PRRs can detect PAMPs in the cytoplasm and assemble inflammasome complexes. Members of the NLR family (such as NLRP1, NLRP6, NLRP3, and others) have been confirmed to assemble inflammasome complexes in response to specific signals and, of these, NLRP3 is the most studied member [69]. Clinical and experimental evidence strongly implicates excessive inflammasome activation and production of IL-1β in the pathogenesis of chronic respiratory diseases, including severe asthma [37,70–72].