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The Role of Toll-Like Receptor Signaling in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Maame Efua S. Sampah, David J. Hackam
The innate immune system consists of multiple protective mechanisms against pathogens provided by the skin, respiratory, and gastrointestinal epithelia. Cellular components such as immunosuppressive erythroid precursors, granulocytes, and neutrophils are also important contributors to this first level of defense. These immune cells recognize potential pathogens via pattern recognition receptors (PRRs), which are transmembrane proteins that recognize extracellular or endosomal pathogen-associated molecular patterns (PAMPs). The most studied example of PRR are TLRs, which interact with their specific PAMP through the MyD88 adapter–dependent pathway, triggering a signaling cascade through NF-κB and the mitogen activated protein (MAP) kinase pathway, ultimately leading to the secretion of proinflammatory cytokines and the expression of costimulatory molecules (9). An alternative TLR signaling pathway may occur via an alternative adapter protein TRIF (10, 11). Hence, TLR stimulation on cells such as macrophages and dendritic cells leads to NF-κB–mediated activation of other cells of the immune system such as T cells and B cells, making TLRs a key bridge between elements of innate immunity and adaptive immunity (10). As will be described in detail later, the first described TLR, namely TLR4, is also expressed on the intestinal epithelium, where it plays an important role in gut development and where its unbridled activation results in mucosal damage and NEC.
Pathogenesis of Tuberculosis
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Divya B. Reddy, Jerrold J. Ellner
TLRs are generally considered to be pro-inflammatory as their ligation leads to nuclear factor (NF)-κb activation. However, TLRs also activate signaling molecules TRIF and IRF increasing expression of IFN-β and an anti-inflammatory response. Relative to monocytes, alveolar macrophages express lower levels of TL-R2, increased TLR-9, and comparable TLR-4. Mycobacterial Ags and even DNA differentially activate TLRs leading to a complex and nuanced response.310
Testicular immunoregulation
Published in C. Yan Cheng, Spermatogenesis, 2018
Fei Wang, Qian Jiang, Daishu Han
PRRs initiate innate immune responses through several signaling pathways (Figure 3.3). TLRs are type 1 transmembrane proteins that may be localized on plasma or endosomal membranes. Most TLRs exclusively initiate the myeloid differentiation protein 88 (MyD88)-dependent pathways, with the exception of TLR3 and TLR4. TLR3 exclusively initiates the Toll/IL-1R-domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway, whereas TLR4 activation triggers both MyD88- and TRIF-dependent pathways.47 The MyD88-dependent pathway predominantly induces the secretion of proinflammatory cytokines and chemokines through the activation of nuclear factor kappa B (NF-κB). The TRIF-dependent pathway activates NF-κB and IFN regulatory factor 3 (IRF3), thereby leading to the induction of proinflammatory cytokines and type 1 IFNs (IFN-α and IFN-β). These cytokines promote the recruitment and activation of leukocytes and the induction of IFN-inducible antiviral proteins, thereby counteracting invading microbial pathogens. Moreover, TLR signaling facilitates the maturation of antigen-presenting cells, thereby directing adaptive immunity. RIG-I and MDA5 are cytosolic RNA sensors and recognize the dsRNA formed by various viruses during replication. RIG-I and MDA5 activation triggers signaling using an adaptor IFN-β promoter stimulator-1 (IPS-1) that is localized to mitochondria.48 The cytosolic DNA sensor signaling pathway requires the stimulator of IFN gene (STING) as a common adaptor localized to the endoplasmic reticulum.49 IPS-1-dependent signaling results in the activation of IRF3 and NF-κB, which induces the expression of type 1 IFNs and proinflammatory cytokines, whereas the STING-dependent pathway predominantly induces type 1 IFN production through the activation of IRF3.
Novel understanding of high mobility group box-1 in the immunopathogenesis of incisional hernias
Published in Expert Review of Clinical Immunology, 2019
Nicholas K. Larsen, Matthew J. Reilly, Finosh G. Thankam, Robert J. Fitzgibbons, Devendra K. Agrawal
TLR2 and TLR4 play a fundamental role in the innate immune systems and are localized to the cell surface where they interact with HMGB-1 [57]. TLR signaling is mainly divided into two pathways, the MyD88 or TRIF dependent pathways. Both TLR2 and TLR4 utilize the MyD88 pathway, but TLR4 can utilize the TRIF pathway as well. MyD88 is recruited to the cell surface and has downstream signals that activate NF-κB and MAPKs/AP1 [58]. On the other hand, the TRIF pathway elicits downstream effects on IRF3. Together these mediators upregulate type I interferon and inflammatory cytokine genes [59,60]. In addition, the binding of a ligand to TLR2 and TLR4 triggers the activation and nuclear translocation of NF-κB and subsequently enhance the expression of the mediators associated with NLRP3 inflammasome.
Synergistic induction of interferon-γ by interleukin-2, interleukin-12 and poly(I:C) in a human natural killer cell line
Published in Immunological Medicine, 2018
Hiroko Majima-Horiuchi, Shihoko Komine-Aizawa, Miki Karasaki-Suzuki, Yasuyuki Izumi, Shin Aizawa, Satoshi Hayakawa
Recently, NK cells have been demonstrated to express TLRs and to directly recognize PAMPs [2–5]. Although both human and murine NK cells have been reported to express the majority of TLRs, whether direct, ligand-mediated TLR activation occurs in NK cells remains controversial [6–8]. Of interest, the requirement of IL-12 for IFN-γ production by TLR stimulation has been reported [5,9]. We and others have reported indispensable roles for IL-2 and IL-12 in the stimulation of lymphokine-activated killer (LAK) cells against choriocarcinoma and autologous tumor cells [10–12]. Therefore, we asked whether the presence of IL-2 and IL-12 would affect TLR3 expression and subsequent TLR3-mediated NK cell activation. In addition, the intracellular signaling of direct NK cell activation via TLR3 has not been revealed yet. Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is an adaptor mediating TLR3 signaling in innate immune cells. Thus, in order to investigate the involvement of TRIF, we used a TRIF inhibitor to block the TRIF pathway.
Evaluation of the Effects of Nobiletin on Toll-Like Receptor 3 Signaling Pathways in Prostate Cancer In Vitro
Published in Nutrition and Cancer, 2021
Asuman Deveci Ozkan, Mehmet Sarihan, Suleyman Kaleli
In order to compare the effects of NOB on TLR3 signaling pathway, the changes in the level of CASP8 were analyzed (Figure 4). Treatment of cells with NOB alone significantly induced the release of CASP8 level in PC-3 cells. Additionally, the level of CASP8 decreased following co-treatment with NOB + Poly I:C compared to NOB or Poly I:C alone group (Figure 4). Thus, the effects of NOB on CASP8 level was less than Poly I:C alone and NOB and Poly I:C group. The obtained results were consistent with the changes in TRIF protein levels.