Protecting Podocyte Injury
Though repulsive guidance cue receptor ROBO2 is important for early kidney development, its role during kidney injury, especially in mature podocytes, is unclear. Using conditional Robo2 knockout mice, Pisarek-Horowitz, Fan, and Kumar et al (Am J Pathol 2020, 799–816) studied this role. Podocyte injury resulted in increased Robo2 expression and podocyte-specific knockout of Robo2 decreased podocyte injury. ROBO2 expression also increases in humans with membranous nephropathy. Increased expression of Robo2 caused podocyte detachment in vitro. ROBO2 may be targeted to manage podocyte injuries and podocytopathies.
Understanding Liver Regeneration
The functional roles of mammalian target of rapamycin complex 2 (mTORC2) during liver regeneration are unclear. By performing partial hepatectomy (PHx) in mice, Xu and Wang et al (Am J Pathol 2020, 817–829) studied these roles. Wild-type mice as well as mice with liver-specific knock out of Rictor—encoding the pivotal unit of mTORC2 complex—were used. Rictor deficient mice were more intolerant to PHx and exhibited higher mortality after PHx. Akt phosphorylation decreased upon Rictor loss, delaying hepatocyte proliferation and lipid biosynthesis along liver regeneration. mTORC2 signaling is necessary for liver regeneration.
Managing Zika Virus–Related Neuroinflammation
Hippo signaling pathway regulates proliferation and differentiation of neural progenitor cells; however, its role in neuronal pathogenesis of Zika virus (ZIKV) is unclear. Using a mouse model and human retinal pigment epithelial cells, Garcia and Paul et al (Am J Pathol 2020, 844–861) studied this role. ZIKV infection activated Hippo pathway and silencing downstream components of Hippo signaling reduced ZIKV replication in vitro. ZIKV infection activated Hippo pathway in the blood brain barrier in the mouse model. The Hippo signaling pathway may be targeted to manage ZIKV-associated ocular and neuronal inflammation.
Exploring Group A Streptococcus Infections
The lack of suitable animal models has limited our understanding of the Group A Streptococcus (GAS) genes responsible for colonization in the primate female genital tract. Using genome-wide transposon mutagenesis screens, Zhu and Olsen et al (Am J Pathol 2020, 862–873) identified potential candidate genes. From the array of genes essential for colonization of the primate vaginal mucosa and infection of the uterine wall identified in vivo and ex vivo, respectively, 39 overlapping genes were identified to be responsible for GAS fitness. Two genes encoding bacterial surface proteins SpyAD and Isp2 were identified to be critical for GAS vaginal colonization, myometrium infection, and necrotizing myositis. These findings open avenues to explore treatments for female GAS genital tract infections.
Understanding Head and Neck Cancer
The mechanisms underlying tumor metastasis to the draining lymph nodes in head and neck squamous cell carcinoma (HNSCC) are unclear. Using HNSCC cells and lymphatic endothelial cells (LECs) as well as a potent anticancer agent, CF3DODA-Me, Kumaravel et al (Am J Pathol 2020, 900–915) explored these mechanisms. The crosstalk between the LECs and HNSCC tumors is mediated via the CXCR3–CXCL11 chemokine axis, which activates many tumor promoting pathways that are abrogated by CF3DODA-Me. CF3DODA-Me may effectively target tumor cells at sites of metastasis and prevent tumor progression via lymphatics.
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Published online: February 18, 2020
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- Loss of Roundabout Guidance Receptor 2 (Robo2) in Podocytes Protects Adult Mice from Glomerular Injury by Maintaining Podocyte Foot Process StructureThe American Journal of PathologyVol. 190Issue 4
- PreviewRoundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS).
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- Hippo Signaling Pathway Has a Critical Role in Zika Virus Replication and in the Pathogenesis of NeuroinflammationThe American Journal of PathologyVol. 190Issue 4
- PreviewZika virus (ZIKV) is a reemerging human pathogen that causes congenital abnormalities, including microcephaly and eye disease. The cellular/molecular basis of ZIKV and host interactions inducing ocular and neuronal pathogenesis are unclear. Herein, we noted that the Hippo/Salvador-Warts-Hippo signaling pathway, which controls organ size through progenitor cell proliferation and differentiation, is dysregulated after ZIKV infection. In human fetal retinal pigment epithelial cells, there is an early induction of transcriptional coactivator, Yes-associated protein (YAP), which is later degraded with a corresponding activation of the TANK binding kinase 1/interferon regulatory factor 3 type I interferon pathway.
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- mTORC2 Signaling Is Necessary for Timely Liver Regeneration after Partial HepatectomyThe American Journal of PathologyVol. 190Issue 4
- PreviewLiver regeneration is a fundamental biological process required for sustaining body homeostasis and restoring liver function after injury. Emerging evidence demonstrates that cytokines, growth factors, and multiple signaling pathways contribute to liver regeneration. Mammalian target of rapamycin complex 2 (mTORC2) regulates cell metabolism, proliferation and survival. The major substrates for mTORC2 are the AGC family members of kinases, including AKT, SGK, and PKC-α. We investigated the functional roles of mTORC2 during liver regeneration.
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- CXCL11-CXCR3 Axis Mediates Tumor Lymphatic Cross Talk and Inflammation-Induced Tumor, Promoting Pathways in Head and Neck CancersThe American Journal of PathologyVol. 190Issue 4
- PreviewTumor metastasis to the draining lymph nodes is critical in patient prognosis and is tightly regulated by molecular interactions mediated by lymphatic endothelial cells (LECs). The underlying mechanisms remain undefined in the head and neck squamous cell carcinomas (HNSCCs). Using HNSCC cells and LECs we determined the mechanisms mediating tumor-lymphatic cross talk. The effects of a pentacyclic triterpenoid, methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me), a potent anticancer agent, were studied on cancer-lymphatic interactions.
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- Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and VirulenceThe American Journal of PathologyVol. 190Issue 4
- PreviewGroup A streptococcus (GAS) is a major pathogen that impacts health and economic affairs worldwide. Although the oropharynx is the primary site of infection, GAS can colonize the female genital tract and cause severe diseases, such as puerperal sepsis, neonatal infections, and necrotizing myometritis. Our understanding of how GAS genes contribute to interaction with the primate female genital tract is limited by the lack of relevant animal models. Using two genome-wide transposon mutagenesis screens, we identified 69 GAS genes required for colonization of the primate vaginal mucosa in vivo and 96 genes required for infection of the uterine wall ex vivo.
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