A hallmark of septic immunosuppression is a reduced number of lymphocytes due to decreased lymphocyte proliferation and increased cell death. A low lymphocyte count referred to as lymphopenia underscores a poor prognosis for septic patients with lower bacterial clearance and second nosocomial infections and death. Epigenetics modulates chromatin architecture to regulate immunity. Despite its importance, the role of epigenetics in septic immunosuppression in terms of lymphopenia remains elusive. In this proposal, we identify that bacteria-elevated Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) is critical for lymphopenia in sepsis; depletion of PRMT4 or inhibition of PRMT4 may attenuate the bacteria-mediated lymphocyte death in cellular and mice models. Our preliminary study shows that bacteria increase PRMT4 at protein level in murine and human lymphocytes. Bacteria reduce an E3 ubiquitin ligase SCF-FBXO9 to promote PRMT4 protein stability and abundance in the cells that leads to lymphocyte death. Depletion of PRMT4 or inhibition of PRMT4 with small molecule reduces bacteria mediated lymphocyte death in cellular and mice septic models. These findings demonstrate an un-described role of a key chromatin modulator PRMT4 in lymphocyte death that may shed lights on novel therapeutic avenue in septic immunosuppression. Therefore, our central hypothesis is that bacteria elevates PRMT4 protein inhibiting its SCF-Fbxo9 mediated proteasomal degradation that causes substantial lymphocyte death to lead immunosuppression; thus inhibition of PRMT4 may attenuate bacteria-mediated lymphocyte death in septic immuno-suppression. To explore this hypothesis we propose the following aims: (i) to determine if bacteria derived endotoxin LPS elevates PRMT4 protein levels by reducing an E3 ubiquitin ligase SCF-Fbxo9; and (ii) to study if elevated PRMT4 leads to substantial lymphocyte death thereby inhibition of PRMT4 may attenuate bacteria-induced septic immunosuppression. These studies will establish the pathophysiological function of a chromatin modulator, PRMT4, as a new effector in lymphocyte death in sepsis. These studies will expand the conceptual groundwork for us to understand how epigenetic regulation plays a central role in the pathogenesis of septic immunosuppression. These studies may serve as a springboard for translational approaches eventually using small molecule therapeutics to target this immune modulator.
Lymphocyte death or lymphopenia is an immunosuppressive hallmark that underscores a poor prognosis for the patients with sepsis. These studies will identify novel molecular mechanisms on how bacterial infection reprograms host immunity at epigenetic level to cause lymphocyte death, which is critical in developing novel therapies directed at ameliorating sepsis and sepsis induced acute lung injury.
