Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection

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Pneumonia remains the leading infectious cause of death worldwide. Ly6Chi monocytes (iMCs) have an essential role in the maintenance of homeostasis and control of pulmonary infection. While it has now been recognized that the functions of iMCs are governed by microenvironment, the impact of local cytokine milieu on iMC function remains elusive. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the most important host cytokines that modulate the functions of iMCs, plays a critical role in host defense against several significant pulmonary pathogens; however, the precise mechanisms by which GM-CSF regulates iMC function to control pulmonary infection is still not fully understood. My recent studies have discovered that GM-CSF promotes inflammatory cytokine production by iMCs and MC-derived cells for control of L. pneumophila infection, and that GM-CSF enhances aerobic glycolysis of MCs which is required for GM-CSF-dependent inflammatory cytokine production ex vivo. The goal of this proposal is to address the critical gap in knowledge regarding the mechanisms underlying GM-CSF-mediated metabolic regulation of iMC function for control of pulmonary infection in vivo. In my preliminary studies, I observed that inhibition of aerobic glycolysis in iMCs exhibited a significant reduction of inflammatory cytokine production during in vivo L. pneumophila infection, and that inhibition of histone acetyltransferase, a key enzyme downstream of Acetyl-CoA metabolism for histone acetylation, abolished GM-CSF-dependent inflammatory cytokine production ex vivo. These preliminary findings provoke the central hypothesis that GM-CSF supports iMC function for control of pulmonary infection through aerobic glycolysis-mediated epigenetic reprogramming. My central hypothesis will be tested by 3 aims: Aim 1 will test the hypothesis that GM-CSF supports iMC functional activities to control L. pneumophila infection. Aim 2 will test the hypothesis that GM-CSF regulates aerobic glycolysis of iMCs, which is required for MC-mediated antibacterial function. Aim 3 will test the hypothesis that aerobic glycolysis supports acetyl-CoA-mediated histone acetylation, which contributes to GM-CSF regulation of MC function. Overall, this proposal will provide insight into the mechanisms underlying GM-CSF-mediated metabolic control of iMC function against bacterial pneumonia.