PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice

Canale, Vinicius; Spalinger, Marianne R.; Alvarez, Rocio; Sayoc-Becerra, Anica; Sanati, Golshid; Manz, Salomon; Chatterjee, Pritha; Santos, Alina N.; Lei, Hillmin; Jahng, Sharon; Chu, Timothy; Shawki, Ali; Hanson, Elaine; Eckmann, Lars; McCole, Declan F.

doi:10.1016/j.jcmgh.2023.03.009

Cited by 5 publications

(2 citation statements)

References 84 publications

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“…87 In addition, loss of the functions and mutation of PTPN2, a key regulator to maintain the vitality and functions of PCs, could accelerate the expansion of inflammatory response. 65,88 In summary, the intestinal tract is not as active as it should be in SAP. The weakness of the intestinal mucus layer, the reduced secretion of AMPs, and the increased abundance of pathogenic bacteria in SAP are closely related to the impaired function of PCs.…”

Section: Goblet Cells (Gcs)mentioning

confidence: 97%

“… 63 Current studies have shown that the reduction of Lgr5+ ISCs in response to intestinal injury is accompanied by the increased secretion of stem cell factors and the enhanced ISCs functions, which is associated with the re-entry of PCs into the cell cycle, the loss of the secretory phenotype, and the acquisition of stem cell properties, which contribute to the regeneration of tissues and the response to the inflammation. 64 , 65 The interaction between ISCs and the immune cells represents a promising therapeutic target in the context of SAP-ALI. 66 …”

Section: Composition Of the Intestinal Mucosal Immune Barriermentioning

confidence: 99%

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Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis

Li,

Wang,

Cao

et al. 2024

JIR

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The pathogenesis of severe acute pancreatitis-associated acute lung injury (SAP-ALI), which is the leading cause of mortality among hospitalized patients in the intensive care unit, remains incompletely elucidated. The intestinal mucosal immune barrier is a crucial component of the intestinal epithelial barrier, and its aberrant activation contributes to the induction of sustained pro-inflammatory immune responses, paradoxical intercellular communication, and bacterial translocation. In this review, we firstly provide a comprehensive overview of the composition of the intestinal mucosal immune barrier and its pivotal roles in the pathogenesis of SAP-ALI. Secondly, the mechanisms of its crosstalk with gut microbiota, which is called gut-lung axis, and its effect on SAP-ALI were summarized. Finally, a number of drugs that could enhance the intestinal mucosal immune barrier and exhibit potential anti-SAP-ALI activities were presented, including probiotics, glutamine, enteral nutrition, and traditional Chinese medicine (TCM). The aim is to offer a theoretical framework based on the perspective of the intestinal mucosal immune barrier to protect against SAP-ALI.

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Section: Goblet Cells (Gcs)mentioning

confidence: 97%

Section: Composition Of the Intestinal Mucosal Immune Barriermentioning

confidence: 99%

Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis

Li,

Wang,

Cao

et al. 2024

JIR

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Ptpn2: A Critical Regulator of Paneth Cell Homeostasis

Theiss¹

2023

Cellular and Molecular Gastroenterology and Hepatology

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Intestinal Epithelial PTPN2 Limits Pathobiont Colonization by Immune-Directed Antimicrobial Responses

Chatterjee,

Spalinger,

Acevedo

et al. 2024

Preprint

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Background and Aims: Loss of activity of the inflammatory bowel disease (IBD) susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), is associated with altered microbiome composition in both human subjects and mice. Further, expansion of the bacterial pathobiont, adherent-invasive E. coli (AIEC), is strongly linked to IBD pathogenesis. The mechanism by which intestinal epithelial cells (IEC) maintain equilibrium between commensal microbiota and immune cells to restrict invading pathobionts is poorly understood. Here, we investigated the role of IEC-specific PTPN2 in regulating AIEC colonization. Methods: Tamoxifen-inducible, intestinal epithelial cell-specific Ptpn2-knockout mice (Ptpn2deltaIEC) and control Ptpn2 fl/fl mice were infected with either non-invasive E. coli K12, or fluorescent-tagged mAIEC (mAIECred) for four consecutive days or administered PBS. Subsequently, bacterial colonization in mouse tissues was quantified. mRNA and protein expression were assayed in intestinal epithelial cells (IECs) or whole tissue lysates by PCR and Western blot. Tissue cytokine expression was determined by ELISA. Intestinal barrier function was determined by in vivo administration of 4 kDa FITC-dextran (FD4) or 70kDa Rhodamine-B dextran (RD70) fluorescent probes. Confocal microscopy was used to determine the localization of tight-junction proteins. Results: Ptpn2deltaIEC mice exhibited increased mAIECred - but not K12 - bacterial load in the distal colon compared to infected Ptpn2fl/fl mice. The higher susceptibility to mAIECfl/fl infection was associated with altered levels of antimicrobial peptide (AMPs). Ileal RNA expression of the alpha-defensin AMPs, Defa5 and Defa6, as well as MMP7, was significantly lower in Ptpn2deltaIEC vs. Ptpn2fl/fl mice, after mAIECred but not K12 infection. Further, we observed increased tight junction-regulated permeability determined by elevated in vivo FD4 but not RD70 permeability in Ptpn2deltaIEC-K12 mice compared to their respective controls. This effect was further exacerbated in Ptpn2deltaIEC mAIEC-infected mice. Further, Ptpn2deltaIEC mice displayed lower IL-22, IL-6, IL-17A cytokine expression post mAIEC infection compared to Ptpn2fl/fl controls. Recombinant IL-22 reversed the FD4 permeability defect and reduced bacterial burden in Ptpn2deltaIEC mice post mAIEC challenge. Conclusion: Our findings highlight that intestinal epithelial PTPN2 is crucial for mucosal immunity and gut homeostasis by promoting anti-bacterial defense mechanisms involving coordinated epithelial-immune responses to restrict pathobiont colonization.

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PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice

Cited by 5 publications

References 84 publications

Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis

Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis

Ptpn2: A Critical Regulator of Paneth Cell Homeostasis

Intestinal Epithelial PTPN2 Limits Pathobiont Colonization by Immune-Directed Antimicrobial Responses

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