Evidence map›Paper›PMID 32909045›Full record

ArticleJournal of Crohn's & colitis2021

The JAK Inhibitor Tofacitinib Rescues Intestinal Barrier Defects Caused by Disrupted Epithelial-macrophage Interactions.

Marianne R Spalinger, Anica Sayoc-Becerra, Christ Ordookhanian, Vinicius Canale, Alina N Santos, Stephanie J King, Moorthy Krishnan, Meera G Nair, Michael Scharl, Declan F McCole

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of Crohn's & colitis, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed, 1 pooled it
5.6field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed, 1 synthesis or guideline pooled it, 74 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 2 countries.

Marianne R SpalingerDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Anica Sayoc-BecerraDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Christ OrdookhanianDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Vinicius CanaleDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Alina N SantosDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Stephanie J KingDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Moorthy KrishnanDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Meera G NairDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
Michael ScharlDepartment for Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
Declan F McColeDivision of Biomedical Sciences, University of California, Riverside, CA, USA.
University of California, Riverside · USUniversity Hospital of Zurich · CH

Funding

A NOVEL ROLE FOR PTPN2 IN INTESTINAL EPITHELIAL BARRIER REGULATIONR01DK091281 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Declan McCole · 2012 to 2026
$5.5M
Tyrosine Phosphatase Regulation of Mucosal Macrophage-Epithelial Cell Cross-talkR01AI153314 · NIAID · UNIVERSITY OF CALIFORNIA RIVERSIDE · PI MCCOLE, DECLAN · 2020 to 2024
$2.5M
Human resistin regulation of inflammation and endotoxic shockR21AI137830 · NIAID · UNIVERSITY OF CALIFORNIA RIVERSIDE · PI NAIR, MEERA GOH · 2018 to 2019
$427k
NIAID NIH HHS R01 AI153314NIAID NIH HHS R21 AI137830NIDDK NIH HHS R01 DK091281
6 · The paper itself

Abstract

BACKGROUND AND

aimsLoss-of-function variants in protein tyrosine phosphatase non-receptor type-2 [PTPN2] promote susceptibility to inflammatory bowel diseases [IBD]. PTPN2 regulates Janus-kinase [JAK] and signal transducer and activator of transcription [STAT] signalling, while protecting the intestinal epithelium from inflammation-induced barrier disruption. The pan-JAK inhibitor tofacitinib is approved to treat ulcerative colitis, but its effects on intestinal epithelial cell-macrophage interactions and on barrier properties are unknown. We aimed to determine if tofacitinib can rescue disrupted epithelial-macrophage interaction and barrier function upon loss of PTPN2.

methodsHuman Caco-2BBe intestinal epithelial cells [IECs] and THP-1 macrophages expressing control or PTPN2-specific shRNA were co-cultured with tofacitinib or vehicle. Transepithelial electrical resistance and 4 kDa fluorescein-dextran flux were measured to assess barrier function. Ptpn2fl/fl and Ptpn2-LysMCre mice, which lack Ptpn2 in myeloid cells, were treated orally with tofacitinib citrate twice daily to assess the in vivo effect on the intestinal epithelial barrier. Colitis was induced via administration of 1.5% dextran sulphate sodium [DSS] in drinking water.

resultsTofacitinib corrected compromised barrier function upon PTPN2 loss in macrophages and/or IECs via normalisation of: [i] tight junction protein expression; [ii] excessive STAT3 signalling; and [iii] IL-6 and IL-22 secretion. In Ptpn2-LysMCre mice, tofacitinib reduced colonic pro-inflammatory macrophages, corrected underlying permeability defects, and prevented the increased susceptibility to DSS colitis.

conclusionsPTPN2 loss in IECs or macrophages compromises IEC-macrophage interactions and reduces epithelial barrier integrity. Both of these events were corrected by tofacitinib in vitro and in vivo. Tofacitinib may have greater therapeutic efficacy in IBD patients harbouring PTPN2 loss-of-function mutations.

Indexed as

AnimalsCell CommunicationCoculture TechniquesDisease Models, AnimalEpithelial CellsHumansInterleukin-22Interleukin-6InterleukinsIntestinal MucosaJanus Kinase InhibitorsMacrophagesMiceMice, KnockoutPiperidinesProtein Tyrosine Phosphatase, Non-Receptor Type 2Interleukin-22Interleukin-6InterleukinsJanus Kinase InhibitorsPiperidinesProtein Tyrosine Phosphatase, Non-Receptor Type 2Ptpn2 protein, mousePyrimidinesSTAT3 Transcription Factortofacitinibepithelial cellsIBDJAK-STATmacrophagepermeabilityTCPTPtight junction

Identifiers

PMID32909045
PMCPMC7944512
OpenAlexW3085001985

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.