Journal article
Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis
Thorax, Vol.78(4), pp.383-393
04/01/2023
DOI: 10.1136/thoraxjnl-2021-217526
PMID: 35354645
Abstract
BackgroundOne hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive.MethodsWe used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models.ResultsWe identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis.ConclusionsThese findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.
Details
- Title: Subtitle
- Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis
- Creators
- Yandong Lai - University of PittsburghXiuying Li - University of PittsburghTiao Li - University of PittsburghXiaoyun Li - University of PittsburghToru Nyunoya - University of PittsburghKong Chen - University of PittsburghGeorgios Kitsios - University of PittsburghMehdi Nouraie - University of PittsburghYingze Zhang - University of PittsburghBryan J McVerry - University of PittsburghJanet S Lee - University of PittsburghRama K Mallmapalli - The Ohio State UniversityChunbin Zou - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Thorax, Vol.78(4), pp.383-393
- DOI
- 10.1136/thoraxjnl-2021-217526
- PMID
- 35354645
- ISSN
- 0040-6376
- eISSN
- 1468-3296
- Publisher
- BMJ Publishing Group Ltd and British Thoracic Society
- Number of pages
- 11
- Grant note
- 5I01CX000105-06; CX001048 / US Department of Veterans Affairs HL081784; HL096376; HL097376; HL098174; HL125435; HL136143; HL142084; HL142997; HL143285; K23 HL139987; P01 HL114453 / National Heart, Lung, and Blood Institute (http://dx.doi.org/10.13039/100000050)
- Language
- English
- Date published
- 04/01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985214172202771
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