PTPN2 Regulates Interactions Between Macrophages and Intestinal Epithelial Cells to Promote Intestinal Barrier Function

Spalinger, Marianne R.; Sayoc-Becerra, Anica; Santos, Alina N.; Shawki, Ali; Canale, Vinicius; Krishnan, Moorthy; Niechcial, Anna; Obialo, Nicole; Scharl, Michael; Li, Jiang; Nair, Meera G.; McCole, Declan F.

doi:10.1053/j.gastro.2020.07.004

Cited by 76 publications

(85 citation statements)

References 45 publications

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“…HT-29.cl19A were obtained from Kim E. Barrett (University of California, San Diego, California), Caco-2BBe, A549 and THP-1 cells were originally obtained from ATCC and cultured according to the manufacturer’s recommendation in medium with 10% FCS. For PTPN2 knockdown, the cells were infected with lentiviral particles containing non-targeting control shRNA (Ctr) or PTPN2-specfic shRNA as described previously 49 and stable clones selected using puromycin. For STAT1 silencing, the cells were transfected with previously validated, STAT1-specific or non-targeting control siRNA constructs (Dharmacon) using DharmaFECT transfectionre agents as described previously 50 .…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Spalinger

Hai

Jiang

et al. 2020

Preprint

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Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)1. While fatality rates are higher among the elderly and those with underlying comorbidities2, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.3–7 We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

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Section: Methodsmentioning

confidence: 99%

Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Spalinger

Hai

Jiang

et al. 2020

Preprint

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“…Tcptp –/– mice die soon after birth as impacted by increased numbers of macrophages in spleen and severe systemic inflammatory disease ( You-Ten et al, 1997 ; Heinonen et al, 2004 ; Scharl et al, 2010a ). Spalinger et al (2020) demonstrated that macrophage-specific TCPTP deficiency increased intestinal permeability via IL-6 release. Besides, Tcptp –/– mice developed B cell deficiency, which was because pre-B cells failed to transit to immature B cells ( You-Ten et al, 1997 ; Doody et al, 2009 ).…”

Section: Main Functions Of Tcptpmentioning

confidence: 99%

“…In response to cytokine stimulation, TC45 shuttles from the nucleus to cytoplasm ( Tiganis et al, 1999 ). TCPTP is capable of regulating pathways in glucose metabolism ( Gurzov et al, 2014 ; Sharp et al, 2015 ; Wiede et al, 2019 ), inflammation control ( Spalinger et al, 2018 , 2020 ; Hsieh et al, 2020 ; Parlato et al, 2020 ), cancer progression ( Stuible et al, 2008 ; Manguso et al, 2017 ; LaFleur et al, 2019 ; Wiede et al, 2020 ) and other biological processes by dephosphorylating distinct substrates ( Bourdeau et al, 2005 ), including Janus activated kinase (JAK), signal transducer and activator of transcription (STAT), receptor tyrosine kinases (RTKs) and others. In the present review, the structure, main substrates (JAK/STAT and RTKs), biological functions of TCPTP, as well as its regulatory role in glucose metabolism are summarized, as an attempt to be referenced for developing treatment strategies of metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

T Cell Protein Tyrosine Phosphatase in Glucose Metabolism

Wang

Liu

Jia

et al. 2021

Front. Cell Dev. Biol.

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T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.

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“…Myeloid cell-specific loss of TCPTP (TCPTP-LysMCre) also enhanced susceptibility to colitis and serum IL-1β levels in mice ( 76 ). Spalinger et al reported that TCPTP loss in macrophages compromises epithelial cell-macrophage interactions and reduces epithelial barrier integrity ( 77 ). Furthermore, TCPTP knockdown in THP-1 cells elevated the IFN-γ-induced secretion of the proinflammatory cytokines IL-6 ( 78 ).…”

Section: Tcptpmentioning

confidence: 99%

“…Macrophages, a significant component of the non-specific immunity, are crucial regulators in bone metabolism and can be regulated by TCPTP ( 77 , 87 , 88 ). The potential influences of TCPTP on osteoimmunology through macrophages can be expounded from four aspects.…”

Section: Tcptp In Osteoimmunologymentioning

confidence: 99%

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

et al. 2021

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Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.

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PTPN2 Regulates Interactions Between Macrophages and Intestinal Epithelial Cells to Promote Intestinal Barrier Function

Cited by 76 publications

References 45 publications

Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

T Cell Protein Tyrosine Phosphatase in Glucose Metabolism

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

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