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Junctional adhesion molecule (JAM) family
Published in C. Yan Cheng, Spermatogenesis, 2018
Extensive and timely restructuring of cell junctions takes place at the interface between adjacent Sertoli cells and between Sertoli cells and germ cells during spermatogenesis. Restructuring of junctions at the blood-testis barrier (BTB) allows the transit of germ cells across the BTB at stage VIII so the germ cells enter the apical compartment for further development. After entering the apical compartment, developing germ cells remain attached to the seminiferous epithelium (Sertoli cells) for physical support and at the same time have to keep migrating toward the tubular lumen for further differentiation. Therefore, cell junctions formed at the BTB and between Sertoli germ cell interface undergo dynamic restructuring. Such restructuring can be achieved by the timely and spatial changes of structural proteins such as occludin, claudin, and junctional adhesion molecules (JAMs), peripheral proteins such as zonula occludens and catenin, as well as signaling molecules including JNK and p38 kinase. JAM is the family of Ca2+-independent cell adhesion molecules found at both the BTB and Sertoli germ cell interface. In this review, we discuss the role of classical JAMs and coxsackievirus and adenovirus receptor (CAR) in the testis as well as their regulatory mechanisms. We highlight some recent findings of classical JAMs and CAR in other tissue models and hope that this information can serve as the blueprint for planning new studies to delineate the unknown functions in the testis and the regulation of JAMs and CAR during spermatogenesis.
Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Although the exact functions and behavior of nIETs remain enigmatic, their primary role seems to be directed toward insuring the integrity of the epithelium and maintaining a local immune balance. TCRγδ nIETs respond to resident bacterial pathobionts that penetrate the epithelial lining by producing antimicrobial factors. Intestinal epithelial cells sensing invasion by bacteria activate resident γδ T cells specifically during the first hours of mucosal penetration. TCRγδ nIETs appeared crucial in preventing commensal bacteria from crossing the mucosal barrier during DSS-induced intestinal damage. This highlights the role for TCRγδ nIETs in maintaining host-microbial homeostasis whenever the intestinal lining has been breached. Additionally, TCRγδ nIETs may produce keratinocyte growth factor and express the junctional adhesion molecule known to induce keratinocyte growth factor upon ligation to its receptor, the Coxsackie virus and adenovirus receptor, thereby linking this costimulatory pathway directly to epithelial repair and maintenance function. In mice lacking all TCRγδ T cells, there are fewer enterocytes and crypt cells, and the enterocytes express less MHC class II. Intestinal infection of TCRδ−/− mice with the protozoan parasite Eimeria vermiformis results in more severe pathology and overt intestinal bleeding. This effect appears to be due to uncontrolled interferon-γ (IFN-γ) production by TCRαβ iIETs. The absence of TCRγδ cells also results in more severe injury in mouse models of colitis, and additionally, keratinocyte growth factor null mice are more susceptible to dextran sulfate sodium colitis suggesting that, in mice, TCRγδ cells control intestinal homeostasis in part by the production of keratinocyte growth factor. TCRγδ nIETs express other regulatory factors such as TGF-β1, TGF-β3, and prothymosin β4, which may aid in epithelial maintenance or repair. TCRγδ nIETs are also equipped with innate and adaptive cytotoxic mechanisms that could contribute to protective immunity. In a model of Toxoplasma gondii infection, TCRγδ nIETs greatly enhanced the protective function of pathogen-specific CD8αβ+ T cells. Furthermore, γδ TCRs may recognize unprocessed antigens such as stress antigens expressed by enterocytes or molecular patterns generated by bacterial nonpeptide antigens, such as phosphorylated nucleotides and prenyl pyrophosphates. In humans, TCRγδ nIETs recognize the highly polymorphic MHC class I chain-related genes MICA and MICB, induced on stressed epithelium, which leads to death of damaged or infected epithelial cells. The invariant NKG2D receptors expressed by TCRγδ nIETs also bind to MICA and MICB, thereby inducing killing in a TCR-independent fashion (see Figure 6.5). Together with their cytotoxic capacity, TCRγδ nIETs produce protective cytokines, such as tumor necrosis factor-α and IFN-γ. Therefore, TCRγδ nIETs not only control the production of IFN-γ by other inflammatory cells, but they can also make IFN-γ that contributes to host protection. Nevertheless, much remains to be learned regarding the function of TCRγδ nIETs, not the least of which is the gap in our knowledge of their ligands for γδ TCRs.
Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Gong et al. developed a pH-responsive polymer vesicle nanocarrier system for tumor-targeted delivery of an anticancer drug and superparamagnetic iron oxide nanoparticles (SPIONs) [769]. The targeted delivery and drug-delivered cytotoxicity were measured by treating nanocomposites to HeLa cell. While the viability of HeLa cells depended on the DOX concentration, a much stronger dependence, however, was observed for HeLa cells incubated with the SPION/DOX-loaded vesicles compared with free DOX. In addition, the cytotoxicity of FA-conjugated SPION/DOX-loaded vesicles was consistently higher than that of FA-free vesicles at all tested DOX concentrations due to the enhanced cellular uptake attributed to FR-mediated endocytosis. Wang et al. synthesized iron oxide nanoparticles encapsulated within pluronic F127 polymer [248]. The surface of nanocomposite was modified with FA, which could selectively target FRs, and Nile red was selected as the anticancer drug. In order to examine the toxicity of Pluronic-coated magnetic nanoparticles (PF127-PAAIO) with or without Nile red, KB cells were incubated 24 h with the magnetic nanoparticles in concentrations ranging from 5 to 1000 mg/mL. Cell viability, as determined by MTT assay, demonstrates that KB cells incubated with PF127-PAAIO or FA-PF127-PAAIO were not affected at all tested concentrations. On the other hand, cell viability decreased profoundly when magnetic nanoparticles were loaded with Nile red. The result obviously demonstrates the effectiveness of folate-mediated cytosis of theranostic nanoparticles. TD: Gene therapy. Application of viral vectors for gene delivery has been extensively studied [573–576]. Suh and Cheon et al. synthesized hybrid nanoparticles for target-specific viral gene delivery [770]. Adenovirus was decorated with manganese-doped iron oxide (MnMEIO) nanoparticles to form a single-particle system with the dual-functional capabilities of target-specific MR imaging and gene delivery (Fig. 16.22). Adenoviruses are known to be highly effective for transferring double-stranded DNAs to various cell types [577–580]. Along with a gene-delivery capability, adenoviruses possess target specificity to the cells with overexpression of Coxsackievirus B adenovirus receptor (CAR), which is known to facilitate the binding and intrusion of adenoviruses to the host cells. Since the adenovirus-MnMEIO nanoparticles possessed the eGFP gene (AdCMVeGFP) inside the adenovirus capsid, release of that gene led to production of eGFP. While no green fluorescence activity was seen from MnMEIO treated U251N cells, vivid green fluorescence was clearly observed from adenovirus-MnMEIO-treated U251N cells, indicating successful gene delivery and expression of eGFP. For the adenovirus-MnMEIO-treated CHO-1 cells with a minimal CAR expression, a weak green fluorescence was observed. Such eGFP expression results are consistent with the target-specific infection of adenovirus-MnMEIO hybrid nanoparticles and MRI results, where higher CAR expression levels were demonstrated by a higher MR contrast and led to higher eGFP expression.
Electrostatic interaction of tumor-targeting adenoviruses with aminoclay acquires enhanced infectivity to tumor cells inside the bladder and has better cytotoxic activity
Published in Drug Delivery, 2018
Soo-Yeon Kim, Whi-An Kwon, Seung-Pil Shin, Ho Kyung Seo, Soo-Jeong Lim, Yuh-Seog Jung, Hyo-Kyung Han, Kyung-Chae Jeong, Sang-Jin Lee
As a human pathogen, 57 serotypes of adenovirus have been identified and classified as A to G subgroups and have been known to be a causative agent for 5–10% of upper respiratory infections in children. Since the genetic materials of the adenoviruses are not incorporated into the host cell's genome post infection, these viruses are ideal for cancer gene therapy. The most commonly used adenovirus vector system is based on serotype 5 of species C. Serotype 5 primarily utilizes the coxsackievirus and adenovirus receptor (CAR) (Roelvink et al., 1998) for initial binding and then interacts with integrin molecules for internalization via clathrin-coated pits. Adenovirus-mediated gene therapy has been promising for treating various cancers and has also been investigated as a therapeutic approach for bladder cancer during previous decades. On top of safer dose-escalation inside the bladder, the intravesical instillation of the virus has demonstrated distinct advantages. First, the adenovirus comes in direct contact with the bladder cancer and, as a result, demonstrates potent anti-tumor activities (successful adenovirus-mediated wild-type p53 gene transfer) in patients with bladder cancer by intravesical vector instillation (Kuball et al., 2002; Benedict et al., 2004). Recent studies further demonstrated that adenovirus gene therapy can be a good combinatorial therapy with well-established standard therapies such as Bacillus Calmette-Guerin (BCG) or chemotherapy (Shieh et al., 2006; Li et al., 2017; Shore et al., 2017). Second, intravesical instillation of adenoviruses also eliminates the need for systemic administration through blood. Avoidance of the systemic circulation minimizes the immune system’s clearance of the virus and avoids viral elimination via liver tropism. However, efficient delivery and selective tumor-targeting still remain major hurdles to this type of treatment in the bladder.
CXCL10-armed oncolytic adenovirus promotes tumor-infiltrating T-cell chemotaxis to enhance anti-PD-1 therapy
Published in OncoImmunology, 2022
Xiaofei Li, Mingjie Lu, Manman Yuan, Jing Ye, Wei Zhang, Lingyan Xu, Xiaohan Wu, Bingqing Hui, Yuchen Yang, Bin Wei, Ciliang Guo, Min Wei, Jie Dong, Xingxin Wu, Yanhong Gu
As an approach to biotherapy for cancer, OVs has attracted researchers’ attention for several decades.18,39 OVs can attack the tumor area in multiple ways: they can infect and lyse the cancer cell directly, and also have the ability to cause collateral destruction within the TME. For instance, they can lead to bystander effect after entering the TME, cause hypoxia environment and develop growth arrest or death in uninfected cells.20,21 That may partially explain why the uninfected areas (EGFP negative areas) also showed low proliferation ability (Supplementary Figure S8). However, many technical challenges exist concerning their application because of toxicity, side effects, and nonspecific replication, among others. In recent years, scientists have tried to address these technical barriers in different ways, such as engineering viruses to specifically infect tumor cells without harming normal cells.18 In our experiment, attenuated type 5 adenovirus (Adv5) lacking the E1B gene was used. Deletion of the E1B gene of Adv5 disabled the ability of Adv5 to downregulate p53 activity, ensuring its specific replication in tumor cells (because most tumors have highly dysfunctional p53 activity) without causing toxicity to normal cells.20,27,40,41 In 2006, China officially approved a modified oncolytic type 5 adenovirus – H101 – to treat head and neck squamous cell carcinoma, also demonstrating the safety of this type of oncolytic virus.27 Notably, Adv5 infects cells by binding coxsackievirus and adenovirus receptor (CAR) of target cells.42 Thus, human cells are susceptible to Adv5 as permissive cells. However, this receptor is absent in most established mouse cell lines, limiting the virus’s ability to infect murine cell lines.43 Therefore, we used the stably transfected mouse colon cancer cell line MC38-CAR to better simulate recombinant oncolytic adenovirus in the human body. Consequently, MC8-CAR cells exhibited significant fluorescence when infected with recombinant adenovirus at an MOI of 10 compared with MC38 wild type (MC38 WT) in vitro (Supplementary Figure S9), and the addition of the CAR (mouse origin) didn’t influence the growth ability of MC38 in vitro, and didn’t show immunogenic response in vivo (Supplementary Figure S10).
Virus-associated disruption of mucosal epithelial tight junctions and its role in viral transmission and spread
Published in Tissue Barriers, 2021
Tight junctions of mucosal epithelium form the physical tissue barrier between epithelial cells that seals the paracellular space and protects the body from the environment9,10,12,15–17 (Figure 2). Tight junctions comprise the integral membrane proteins of the claudin family, which has 27 members and is responsible for the formation of tight junction strands, i.e., heteropolymers, which are embedded within the plasma membrane, to delineate the border between the apical and basolateral membrane domains.18–20 Tight junctions also have other proteins, including occludin, tricellulin, and MarvelD3, which are a staple of tight junctions, responsible for their maintenance and regulation of function.21–23 The transmembrane proteins occludin and the claudins are associated with the PDZ domain, which contains the cytoplasmic proteins zonula occludens-1 (ZO-1), −2, and −324,25 (Figure 2). The zonula occludens mediate linkage of occludin and claudins to the actin cytoskeleton.26 Other cytoplasmic tight junction-associated proteins, including cingulin, PALS1 (the protein associated with Lin-seven 1), MUPP1 (multi-PDZ domain protein 1), MAGI1 and −2 (membrane-associated guanylate kinase), PATJ (the protein associated with tight junctions), ASIP/PARS3, and Par6, play a role in the interaction of transmembrane tight junction proteins with the actin cytoskeleton and in the regulation of tight junction signaling.27–30 Interaction of the transmembrane tight junction proteins facilitates the formation of tight junctions between adjacent epithelial cells near the apical surface, sealing the paracellular space between epithelial cells.31 Junctional adhesion molecules 1 (JAM-1), −2, and −3 and coxsackievirus and adenovirus receptor (CAR) are immunoglobulin family members with single transmembrane domains. These domains are specifically localized at the tight junctions of epithelial cells and are involved in the regulation of junctional integrity and paracellular permeability32 (Figure 2). JAM-1, which is directly bound and sequestered in the epithelial tight junction areas, regulates paracellular permeability and tight junction resealing.32–38 An adhesion protein, nectin-1, is also localized within the epithelial junctions and serves as a receptor for herpes simplex virus (HSV).39–41 Intercellular adherens junctions are formed by homotypic interaction of the transmembrane protein E-cadherin, which is connected to intracellular proteins p120 and β and α catenins and the actin cytoskeleton.42 Both tight and adherens junctions are connected through the actin cytoskeleton.42