Regulation der Myelinphagozytose durch Makrophagen/Mikroglia
Zusammenfassung der Projektergebnisse
Macrophages are key effectors in demyelinating diseases of the central and peripheral nervous system by phagocytosing myelin and releasing immunoregulatory mediators. Here, we report on a distinct, a priori anti-inflammatory reaction of macrophages phagocytosing myelin upon contact with damaged nerve tissue. Macrophages rapidly invaded peripheral (sciatic) and central (optic) nerve tissues in vitro, readily incorporated myelin and expressed high levels of phagocytosis-associated molecules (e.g. Fc and scavenger receptors). In contrast, factors involved in antigen presentation (MHC-classII, CD80, CD86) revealed only a restricted expression. In parallel, a highly ordered appearance of cytokines and chemokines was observed. IL-10, IL-6, CCL22 and CXCL1 were immediately but transiently induced, while levels of CCL2, CCL11 and TGFbeta were more persistent. Such a profile would attract neutrophils, monocytes/macrophages and Th2 cells, as well as bias for a Th2-supporting environment. Importantly, pro-inflammatory/Th1-supporting factors, such as TNFalpha, IL- 12p70, CCL3 and CCL5, were not induced. Still the simultaneous presence of TGFbeta and IL-6 could assist Th17 development, further depending on still non-present IL-23. However, we can ascertain that the modulation of IL-6 activity, by the use of IL-6 or IL-6 receptorblocking antibodies, did not lead to a modified migration or to phagocytotic activities of the macrophages when confronting damaged nerve tissues. IL-6 on its own can thus not be the sole trigger for the cascade of events described here. Taken together, the release pattern was clearly distinct from reactive phenotypes induced in isolated macrophages and microglia upon treatment with IL-4, IL-13, bacterial lipopolysaccharide, IFNgamma or purified myelin. Nerve-exposed macrophages thus commit to a unique functional orientation. Macrophage phenotype commitment in human multiple sclerosis lesions Recently, a detailed study by Boven et al. (2006) reported on the detection of cytokines and chemokines by immunostaining within lesions of MS patients. Overall, the milieu generated by injured nerves and invading macrophages in our work is very similar to the antiinflammation-biased environment found in MS lesions. This is in accordance with the observation that remyelination in MS lesions generally occur in the presence of macrophages. Taken together, our study and the report on MS lesions complement and support each other extremely well in demonstrating the anti-inflammatory phenotype orientation of macrophagelike cells engaged in myelin phagocytosis from damaged nerve tissue. Some earlier experimental evidence reported in animal models of multiple sclerosis (e.g. EAE) suggested a relatively pro-inflammatory reaction for macrophages. Our data do not support these original observations but are consistent with the characterization of macrophages that has been recently described in human MS lesions. It should be kept in mind that the activation status of macrophages can vary according to the stage of the disease development. Further experiments are thus essential to delineate the activation profile of macrophages and microglia and especially the factors that modulate this dynamic scenario.
Projektbezogene Publikationen (Auswahl)
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Phenotypic diversity of microglia and macrophages. (2006) The 8th International Congress of Neuroimmunology, Symposium ‘Alzheimer’s disease, neurodegeneration and immunity’. Nagoya, Japan, J Neuroimunol 178 Suppl 1: 19
Uwe-Karsten Hanisch
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Phenotypic diversity of microglia and macrophages: Changing a stereotyp(d) concept. (2006) 4th Neuroimmunology and brain inflammation postgraduate course, Nordic Center of Excellence in Neurodegeneration and A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland
Uwe-Karsten Hanisch
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Die Rolle von Interleukin-6 beim Myelinabbau durch Makrophagen. Dissertation, (2007) Georg-August-Universität zu Göttingen
Sören-Wibo Hilbert
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Phenotypic diversity of microglia and macrophages. (2007) University of Aberdeen, School of Medical Sciences, College of Life Sciences and Medicine, Aberdeen
Uwe-Karsten Hanisch
