Research directed at understanding the expression and regulation of inflammatory mediators and their subsequent biological activities represent major investigative directions of my laboratory. A general theme of the laboratory is an assessment of the mechanistic involvement of cytokine and chemokine cascades that direct the initiation and maintenance of the immune response. Recently our laboratory has established a program to determine the role epigenetics play in controlling the inflammatory phenotype of various lymphoid and myeloid cells. We have determined that certain cytokines can influence the expression of chromatin modifying enzymes, which subsequently sets an epigenetic signature in T cells, macrophages, and dendritic cells. These chromatin modifications are one of the mechanisms that allows for transcriptionally active or suppressed transcription needed to appropriately drive an immune response. We have also utilized inducible knockout animals where specific chromatin modifying enzymes have been silenced and have shown that experimental models of acute and chronic inflammation have dramatic outcomes as compared to their wild type controls. Additional efforts in the laboratory has focused on the notch and notch ligand system as major mechanisms for the activation of immune reactive during Mycobacterial antigen challenge or challenge with H1N1 influenza. In models of Mycobacterium challenge, delta like 4 ligand (DLL4) is expressed on dendritic cells and drive the maturation of Th17 cells, while in the H1N1 model delta like 1 expression on macrophages is a key mechanism to activate Th1 cells. In total, our research aims focus on molecular mechanisms that result in the initiation and maintenance of inflammatory disease.
Ito T, Allen RM, Carson WF, Schaller M, Cavassani KA, Hogaboam CM, Lukacs NW, Matsukawa A, Kunkel SL. The critical role of notch ligand delta like 1 in the pathogenesis of influenza A virus (H1N1) infection. PLoS Pathog 2011 Nov 7 e1002341 PMID 22072963.
Shimizu-Hirota R, Xiong W, Baxter BT, Kunkel Sl, Maillard I, Chen XW, Sabeh F, Liu XY, Weiss SJ. MT1-MMP regulates the PI3K .Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 2012 26:395-413. PMID 22345520.