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Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) induced monocyte subsets and their potential influence on intestinal inflammation

Applicant Professor Dr. Dirk Föll, since 11/2012
Subject Area Pediatric and Adolescent Medicine
Term from 2010 to 2016
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 172325050
 
Final Report Year 2015

Final Report Abstract

In recent years it became apparent that the interplay of innate and adaptive immunity requires tight regulation to prevent autoimmunity and chronic inflammation. Moreover, the paradigm that chronic inflammatory conditions e.g. Crohn’s disease (CD) and arthritis are mediated by cells of the adaptive immune system has been challenged by recent observations showing that cells of the innate immune system also play a crucial role in induction or perpetuation of these conditions. With our studies we could show that monocytes, which were thought to be less effective in active CD patients, are phenotypically not altered, nor functionally impaired, in quiescent CD patients. In addition, we could show that GM-CSF that exerts beneficial effects in the treatment of some CD patients acts in a comparable way on healthy and CD blood monocytes. Even more interestingly, we showed that short term treatment of monocytes with GM-CSF leads to a phenotype shift with features of M2-like macrophages, but also features of M1-like macrophages represented by increased oxidative burst and response to secondary microbial stimuli. We therefore termed these cells “GMaM”. In murine experimental colitis models GMaM showed therapeutic activity. This was accompanied by GMaM interaction with intestinal T cells shaping their differentiation towards Th2 by upregulating IL-4, IL10 and IL13 and downregulating IFNγ. Additionally, increased numbers of Treg cells were found in GMaM treated mice. By performing in vivo and in vitro experiments we could show that highly expressed CD39 and CD73 on the surface of GMaM are responsible for Treg induction. Hence, it is conceivable that beneficial effects of GM-CSF in CD may possibly be mediated through reprogramming of monocytes to simultaneously improve bacterial clearance and induce wound healing, as well as regulation of adaptive immunity e.g. by induction of Th2 and Treg cells to limit excessive inflammation. Additionally, we could show that co-stimulation of monocytes with GM-CSF and IFNγ leads to a proinflammatory form of activation-induced cell death (AICD). We found the underlying mechanism to be cathepsin B dependent. In addition, recent publications showed that RA patient synovial fluid (SF) contains significantly more T cells that produce both GM-CSF and IFNγ. We could link these two observations, as we also found arthritic joints to be enriched with GM-CSF/IFNγ co-expressing T cells. Moreover, cathepsin B-activity was increased in monocytes isolated from SF from patients with active JIA. Hence, AICD could be a relevant response mechanism or a form of regulation of hyperactivated monocytes in arthritic joints that are enriched with GM-CSF/IFNγ co-expressing T cells. In summary, our data support the concept of an important interplay between innate and adaptive immunity in chronic-inflammatory diseases. Furthermore, an immune-regulatory function of GMaM contributes to the outcome of inflammation in these conditions. Further studies will enable us to exploit these mechanisms for potential therapeutic implications.

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