Die Rolle von Makrophagen in Entzündungen und Tumoren: neue Stabilin-1-vermittelte Prozesse

Zusammenfassung

Makrophagen sind die entscheidenden Zellen bei der Initiation, Progression und Modulation inflammatorischer Reaktionen. Im gesunden Gewebe sorgen Makrophagen für eine homöostatische Balance. Zur Erfüllung ihrer Funktionen sind Makrophagen weit verbreitet: in großer Zahl kommen Makrophagen in lympho-hämatopoetischen Organen, in anderen differenzierten Geweben wie Lunge, Darm und Haut und in der Plazenta vor. Hier kommunizieren sie mit anderen Zellen über zahlreiche Oberflächenrezeptoren und lösliche Mediatoren. Alternativ aktivierte Makrophagen (M2) spielen eine Schlüsselrolle in der Initiation und Regulation anti-inflammatorischer Prozesse, in der Induktion von Heilungsprozessen sowie auch in Tumorprogression und Metastasierung. M2 werden in vitro durch das Th2-Zytokin IL-4 und durch Glukokortikoide induziert. Stabilin-1 ist ein Multidomänenprotein, das selektiv von M2 exprimiert wird. Wir konnten hier zeigen, dass Stabilin-1 ein spezieller Scavenger-Rezeptor ist und zwei Funktionen in alternativ aktivierten Makrophagen besitzt: Endozytose und intrazelluläre Sortierung. In M2 vermittelt Stabilin-1 einen neuen Prozess - die Internalisierung von SPARC, nicht-strukturelle Komponente der extrazellulären Matrix, der als entscheidender Regulator von Entwicklungsprozessen, Gewebeumbau, Angiogenese, Wundheilung und Tumoraggressivität funktioniert. Andererseits funktioniert Stabilin-1 als Sortierungsrezeptor für das neue Chitinase-ähnliche Protein SI-CLP und transportiert es zu dem lysosomalen Sekretionsweg. Die Identifikation von Stabilin-1 als Sortierungsrezeptor für SI-CLP ist das erste bekannte Beispiel für einen lysosomalen Sortierungsprozess, der speziell in alternativ aktivierten Makrophagen stattfindet. Makrophagen stellen eine Hauptproduktionsquelle für das Vorkommen verschiedener menschlicher Chitinasen und Chitinase-ähnlichen Proteine, die als Biomarker für Entzündungen und Tumoren dienen. Der von uns neu generierte monoklonale Rattenantikörper 1C11 gegen SI-CLP detektiert das Protein mit einer hohen Spezifität in menschlichem Gewebe und in peripheren Blutleukozyten und wird als Werkzeug für die Untersuchung von SI-CLP-assoziierten Erkrankungen dienen. SI-CLP ist auch ein potenzieller Marker für die individuelle Sensitivität von Patienten gegenüber Glukokortikoiden und für die Vorhersage der Nebenwirkungen der Glukokortikoidtherapie.

Abstract

Macrophages are essential cells for the initiation, progression and modulation of inflammatory reactions. Macrophages control homeostatic balance in healthy tissues. To fulfill their functions, macrophages appear in high amounts in lymph-hematopoetic organs, in differentiated tissues like lung, intestine and skin as well as in placenta. Macrophages use surface molecules and soluble mediators to communicate with other cell types. Alternatively activated macrophages (M2) play a key role in the initiation and regulation of anti-inflammatory processes, induction of healing as well as in tumour progression and metastasis. In vitro alternatively activated macrophages can be induced with Th2 cytokine IL-4 and gluococorticoids. Stabilin-1 is a multidomain protein which is selectively expressed by M2. We were able to show that stabilin-1 is a specific scavenger receptor and has dual function in alternatively activated macrophages: endocytosis and intracellular sorting. Stabilin-1 mediates a new process in M2: internalization for SPARC, a non-structural component of extracellular matrix which functions are critical for the developmental processes, tissue turn-over, angiogenesis, wound-healing and tumor progression. At the same time stabilin-1 functions as intracellular sorting receptor of new chitinase-like protein SI-CLP and delivers it to the lysosomal secretory pathway. Identification of stabilin-1 as a sorting receptor for SI-CLP is a first known example of lysosomal sorting process which is specific for alternatively activated macrophages. Macrophages are the major source for production of human chitinases and chitinase-like protein which are used as biomarkers for different inflammatory disorders and tumours. The newly generated monoclonal rat antibody 1c11 against SI-CLP monoclonal recognizes the protein in tissues and in peripheral blood leukocytes and can be used to search for the association of SI-CLP with diseases. SI-CLP can be also considered as potential marker for the individual sensitivity to glucocorticoids and for prediction of side effects of glucocorticoid-therapy.

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