genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
are effectively cleared by Kupffer cells and sinusoidal endothelial cells (Limmer et al. 2000,
Maemura et al. 2005, van Oosten et al. 2001).
Physiologically, there is no detectable intrahepatic immune activation in response to the low
amount of microbial agent and food antigens derived from the gut because of a tolerogenic
environment (Limmer et al. 2000, Macpherson et al. 2002). However, when the antigenic
challenge is increased, an inflammatory response with a recruitment of neutrophils,
monocytes/macrophages, and lymphocytes may be induced (Wiegard et al. 2005). Then, an
increased production of inflammatory mediators such as reactive oxygen species (ROS) may
cause cell damage and loss of hepatocyte functions (Ott et al. 2007).
To elucidate hepatic immune regulatory pathways that may contribute to chronic
psychological stress-induced immune suppression, the hepatic gene expression profiling was
used to analyze expression changes of immune response and cell survival genes in stressed and
non-stressed mice (Depke et al. 2009).
Gene expression pattern of bone-marrow derived macrophages after interferon-gamma
activation
In the innate immune system, macrophages, together with dendritic cells, hold a central
position. They are main effectors of the clearance of infections by their sentinel and phagocytic
function. Macrophages present phagocytosed antigen derived peptides on MHC-II to
lymphocytes. By this function, macrophages take part in regulation of the adaptive immune
response (Gordon S 2007). Phagocytosis is mediated by different receptors like complement
receptors, mannose receptor or via the interaction between lipopolysaccharide (LPS), LPS-binding
protein (LBP), CD14, and Toll-like receptor TLR (Janeway/Medzhitov 2002, Greenberg/Grinstein
2002). Upon binding of ligands to TLR, macrophages secrete chemokines like CXCL8, CXCL10,
CCL3, CCL4, and CCL5, which mediate chemotaxis of neutrophils, NK cells, and T cells (Luster
2002). Additionally, pro-inflammatory cytokines like TNF-α and IL-1 secreted by macrophages
further contribute to inflammation. Macrophages promote extracellular matrix degradation by
their matrix metalloproteinases, MMPs (Gibbs et al. 1999a, 1999b). They exhibit increased killing
activity towards phagocytosed pathogens during respiratory burst, which is among others
mediated by toxic, reactive defense molecules like NO and O –
2 produced by inducible NO
synthase (iNOS) and NADPH oxidase, respectively (DeLeo et al. 1999, Iles/Forman 2002, Kantari
et al. 2008, MacMicking et al. 1997, Mori/Gotoh 2004, Park JB 2003). This macrophage
phenotype corresponds to the classical activation and initiates primarily a Th1-based immune
response (Fig. I.6). Vice versa, IFN-γ as part of the Th1 cytokine pattern provokes such classical
activation (Duffield 2003).
After a phase of inflammatory activation and phagocytosis of apoptotic cells at the site of
inflammation, macrophages are able to switch their functional profile now aiming to reduce
inflammation by anti-inflammatory cytokines, stop matrix degradation and even assist healing by
production of fibronectin and tissue transglutaminase. A similar phenotyp with reduced
intracellular killing of pathogens is observed after activation by Th2 cytokines like IL-4 and TGF-β.
Activation leading to this phenotype is called “alternative” (Duffield 2003). Macrophages can be
activated in a third way, called type II activation. This activation needs ligand binding to Fcγ
receptors in combination with an activating stimulus like that mediated by TLRs. Afterwards, the
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