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.
Schaller MA, Logue H, Mukherjee S, Lindell DM, Coelho AL, Lincoln P, Carson WF, Ito T, Cavassani KA, Chensue SW, Hogaboam CM, Lukacs NW, Kunkel SLDelta-like 4 differentially regulates murine CD4 T cell expansion via BmI1. Plos ONE 2010 17;e12172PMID 20808960
Carson WF 4th, Cavassani KA, Dou Y, Kunkel Sl. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics, 2011; 6:8-18 PMID 21048427.
Carson WF 4th, Ito T, Schaller M, Cavassani KA, Chensue SW, Kunkel SL. Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2 –mediated granulomatous lung inflammation. PLos One 2011; 6(5):e20385 PMID 21655295.
Frantz FG, Ito T, Cavassani KA, Hogaboam DM, Lopes Silva C, Kunkel SL, Faccioli LH. Therapeutic DNA vaccine reduces schistosoma mansoni-induced tissue damage through cytokine balance and decreased migration of myofibroblasts. Am J Pathol 2011; 179:223-229. PMID 21703404
Tarraosn G, Auli M, Mustafa S, Dolgachev V, Domenech MT, Prats N, Dominguez M, Lopex R, Aguilar N, Calbet M, Point M, Milligan G, Kunkel Sl, Godessart N. The sphingosine-1 phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice. Int Immunopharmacol 2011 (Epub) PMID 21798372
Carson WF Kunkel SL. Monocytes to functional dendritic cells is often a bridge too fare for cancer therapy. Transl. Res. 2011; 158:197-199, PMID 21925116.
Moreira AP, Cavassani KA, Ismailoglu UB, Hullinger R, Dunleavy MP, Knight DA, Kunkel SL, Uematsu S, Akira S, Hogaboam CM. The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL17A. J Clin Invest 2011; PMID 22005301.
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.
Carson, WFand Kunkel SL. Molecular mechanism underlying severe sepsis- Insights from epigenetics. Annual Update in intensive care and emergency medicine. Springer –Verlag Ed. Jean-Louis Vincent pp. 3-12
Ishii M, Asano K, Namkoong H, Tasaka S, Mizoguchi K, Asami T, Kamata H, Kimizuka Y, Fujiwara H, Funatsu Y, Kagawa S, Miyata J, Ishii K, Makamura M, Hirai H, Nagata K, Kunkel SL, Hasegawa N, Betsuyaku T. CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. J. Immunol, 2012; 188:5655-5664. PMID 22544936.
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.