Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis

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.

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

“…As a result, in lymphoma cell lines stimulated with LPS, CARM1 expression is augmented, triggering caspase 3 activation, resulting in lymphocyte cell death. Similar results are obtained in spleens of mice injured either with LPS or in a polymicrobial sepsis model [ 57 ]. The activation of MHC II through CIITA-dependent transcription is enhanced by the methyltransferase activity of CARM1, as also demonstrated for PRMT1 [ 39 ].…”

The Influence of Arginine Methylation in Immunity and Inflammation

“…However, a recent study has shown that CARM1 is implicated in lineage differentiation for both B and T cells. 67 LPS stimulation was found to increase CARM1 expression in B and T lymphocytes as well as monocytes that mediate caspase-3-dependent lymphocyte cell death. 67 Inhibition of CARM1 activity using TP-064 attenuated lymphocyte cell death and protected mice following LPS lung injury and polymicrobial sepsis.…”

“… 67 LPS stimulation was found to increase CARM1 expression in B and T lymphocytes as well as monocytes that mediate caspase-3-dependent lymphocyte cell death. 67 Inhibition of CARM1 activity using TP-064 attenuated lymphocyte cell death and protected mice following LPS lung injury and polymicrobial sepsis. 67 Moreover, CARM1 was shown to downregulate microRNA (miRNA) 223 (miR-223) expression via the methylation of runt-related transcription factor 1 (RUNX1) at residue R223 and lead to the recruitment of double PHD finger 2 (DPF2) to repress myeloid differentiation.…”

“… 67 Inhibition of CARM1 activity using TP-064 attenuated lymphocyte cell death and protected mice following LPS lung injury and polymicrobial sepsis. 67 Moreover, CARM1 was shown to downregulate microRNA (miRNA) 223 (miR-223) expression via the methylation of runt-related transcription factor 1 (RUNX1) at residue R223 and lead to the recruitment of double PHD finger 2 (DPF2) to repress myeloid differentiation. 68 Strikingly, CARM1 overexpression inhibited the differentiation of adult hematopoietic stem cells (HSCs) in culture, while CARM1 knockdown promoted their differentiation.…”

Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

“…Lai et al have recently reported the role of protein arginine N-methyltransferase4 (PRMT4) (also known as coactivatorassociated arginine methyltransferase 1), a chromatin modulator, during the septic immunosuppressive process, which reveals a pathway of epigenetic enzyme induced lymphocytes deaths. Upregulated expression of PRMT4 is found in both lymphocytes and monocytes under LPS stimuli or sepsis, whereas it shows more pronounced in activated T cells and explicitly facilitates lymphocytes apoptosis via caspase 3 signaling [116].…”