Christian W. Schindler, MD, PhD
Characterization of the potent antiviral activity associated with Interferons (IFNs), which were discovered over 50 years ago, has punctuated several notable milestones in molecular immunology, including elucidation of the JAK-STAT signaling pathway. In this signaling paradigm, JAKs are receptor associated tyrosine kinases and STATs (Signal Transducers and Activators of Transcription) the transcription factors they activate. Subsequent studies have identified 7 STATs and 4 JAKs, providing important insight into how the ~50 members of the four-helix bundle cytokine family transduce their potent biological responses. This includes the regulation of several developmental pathways, as well as the innate and adaptive limbs of the immune system. Interests in the laboratory include understanding the critical role IFNs play in regulating innate immunity, Stat3's intriguing development activity, as well as the critical role macrophages and the innate immune system play in the development of chronic inflammatory disease, like atherosclerosis. More recent efforts have begun to explore the role mononuclear phagocytes (i.e., macrophages) play in tissue homeostasis.
IFNs: Type I IFNs (IFN-Is; e.g., IFN-alpha), widely recognized for their antiviral activity (innate immunity), signal through Stat1 and Stat2, whereas type II IFN (i.e., IFN-gamma) signals exclusively through Stat1. Exploiting STAT and IFN receptor knockout mice has provided an opportunity to explore how IFNs regulate immunity. Recent studies have highlighted the critical role IFN-Is play in the innate response to bacterial, as well as viral pathogens. These studies have identified a sophisticated set of innate pattern recognition receptors (PRR) that recognize specific pathogen associated molecular patterns (PAMPs), culminating in the secretion of IFN-Is, as well as other inflammatory cytokines. An important effort in the laboratory entails exploring how the large IFN-I family (includes ~20 members) direct distinct biological responses, including an effective innate response to Legionella pneumophila, the causative agent of Legionnaires' Disease.
Stat3: In contrast to the other mammalian STATs, Stat3 has been highly conserved throughout evolution and implicated in the development and homeostasis of several cell lineages. Currently, tissues specific and conditional Stat3 gene targeting strategies are being exploited to understand the role Stat3 plays in immune homeostasis and tumorigenesis.
Mononuclear phagocytes: Macrophages, which are distributed in most tissues, serve as immune sentinels, initiating a broad array of inflammatory responses to invading microbes. However, they also play an important role in directing the resolution of acute inflammatory events. Likewise, they may also regulate tissue homeostasis during non-infectious stresses. A better understanding of how macrophages direct tissues repair and homeostasis should provide important insight into the pathogenesis of a number of chronic inflammatory diseases. Currently, the laboratory is focused on developing genetic models to study the complex relationship macrophages and the tissues they reside in.
Farlik, M., Reutterer, B., Schindler, C., Greten, F., Vogl, C., Muller, M. and Decker, T. (2010) Nonconventional initiation complex assembly by STAT and NF-kappaB transcription factors regulates nitric oxide synthase expression. Immunity 33: 25-34.
Melillo, J.A., Song, L., Bhagat, G., Blazquez, A.B., Plumlee, C.R., Lee, C., Berin, C., Reizis, B. and Schindler, C. (2010) Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J. Immunol. 184: 2638-2645.
Plumlee, C.R., Lee, C., Beg, A.A., Decker, T., Shuman, H.A. and Schindler, C. (2009) Interferons direct an effective innate response to Legionella pneumophila infection. J. Biol. Chem. 284: 30058-30066.
Martin, F.J., Gomez, I.M., Wetzel, M., Memmi, G., O'Seaghdha, M., Soong G., Schindler, C. and Prince, A. (2009) S. aureus activates type I IFN signaling through the Xr repeated sequences of protein A. J. Clin. Invest. 115: 1931-1939.
Zhao, W., Lee, C., Piganis, R., Plumlee, C., de Weerd, N., Hertzog, P.J. and Schindler, C. (2008) A conserved IFN-alpha receptor tyrosine motif directs the biological response to type I IFNs. J. Immunol. 180: 5483-5489.
Schindler, C. and Plumlee, C. (2008) IFN-Is pen the JAK-STAT pathway. Sem. Cell Dev. Biol. 19: 311-318.
Zhao, W., Cha, E.N., Lee, C., Park, C.Y. and Schindler, C. (2007) Stat2-dependent regulation of MHC class II expression. J. Immunol. 179: 463-471.
Schindler, C., Levy, D.E. and Decker, T. (2007) JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282: 20059-20063.
Kisseleva, T., Song, L., Vorontchikhina, M., Feirt, N., Kitajewski, J. and Schindler, C. (2006) NFkB regulation of endothelial cell function during LPS toxemia and cancer. J. Clin. Invest. 116: 2955-2953.
Song, L., Battacharya, S., Yunis, A.A., Lima, C.D. and Schindler, C. (2006) SUMO modification of Stat1. Blood 108: 3237-3244.
Song, L., Leung, C. and Schindler, C. (2001) Lymphocytes are important in atherosclerosis. J. Clin. Invest. 108: 251-259.
Park, C., Li, S., Cha, E. and Schindler, C. (2000) Immune response in Stat2 knock-out mice. Immunity 13: 795-804.
Azam, M., Lee, C., Strehlow, I. and Schindler, C. (1997) Functional distinct isoforms of Stat5 are generated by protein processing. Immunity 6: 691-701.
Gupta, S., Pablo, A.M., Jiang, X-c., Wang, N., Tall. A.R. and Schindler, C. (1997) IFN-gamma potentiates atherosclerosis in apoE knock-out mice. J. Clin. Invest. 99: 2752-2761.
Schindler, C., Shuai, K., Prezioso, V. and Darnell, J.E. (1992) Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257: 809-813.