Evidence map›Paper›PMID 25104775›Full record

ArticleAnnals of the rheumatic diseases2015

Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.

Jason S Knight, Venkataraman Subramanian, Alexander A O'Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Carolyne K Smith, Jeffrey B Hodgin, Paul R Thompson, Mariana J Kaplan

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

Article in Annals of the rheumatic diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 301 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
301citing papers in PubMed, 1 pooled it
10.7field-weighted citation impact, top 1% 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

301 citing papers in PubMed, 1 synthesis or guideline pooled it, 421 citations in OpenAlex.

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241 more citing papers are in PubMed but not listed here.

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

9 authors at 4 institutions in 1 country.

Jason S KnightDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Venkataraman SubramanianDepartment of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA.
Alexander A O'DellDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Srilakshmi YalavarthiDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Wenpu ZhaoSystemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Carolyne K SmithSystemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Jeffrey B HodginDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Paul R ThompsonDepartment of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA.
Mariana J KaplanSystemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
University of Michigan–Ann Arbor · USNational Institutes of Health · USScripps Research Institute · USNational Institute of Arthritis and Musculoskeletal and Skin Diseases · US

Funding

Systemic AutoimmunityZIAAR041199 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI KAPLAN, MARIANA · 2014 to 2025
$32.5M
Haloacetamidine based inactivators of Protein Arginine Deiminase 4R01GM079357 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI THOMPSON, PAUL R · 2007 to 2016
$3.3M
NETs in the development of lupus and its cardiovascular complicationsR01HL088419 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI EITZMAN, DANIEL T · 2009 to 2016
$3.1M
Targeting Protein Arginine Deiminases to Prevent Colitis and Colon CancerR01CA151304 · NCI · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · PI HOFSETH, LORNE J, THOMPSON, PAUL R · 2011 to 2015
$1.6M
Intramural NIH HHS Z99 AR999999NCI NIH HHS CA151304NCI NIH HHS R01 CA151304NHLBI NIH HHS HL088419NHLBI NIH HHS R01 HL088419NIGMS NIH HHS GM079357NIGMS NIH HHS R01 GM079357
6 · The paper itself

Abstract

objectivesAn imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs--knockout of NOX2--accelerates lupus in a different murine model, MRL/lpr. Here, we test the effects of PAD inhibition on MRL/lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE.

methodsNET formation and autoantibodies to NETs were characterised in lupus-prone MRL/lpr mice. MRL/lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice.

resultsNeutrophils from MRL/lpr mice demonstrate accelerated NET formation compared with controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease.

conclusionsPAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.

Indexed as

AmidinesAnimalsDisease Models, AnimalEnzyme-Linked Immunosorbent AssayExtracellular TrapsHydrolasesKidney DiseasesLupus Erythematosus, SystemicMiceMice, Inbred MRL lprProtein-Arginine DeiminasesVascular DiseasesAmidinesHydrolasesProtein-Arginine DeiminasesAutoimmune DiseasesAutoimmunitySystemic Lupus Erythematosus

Identifiers

PMID25104775
PMCPMC4320672
OpenAlexW2159514587

What OpenQuestion holds

Textmetadata
LicenceTDM
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.