Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) induced monocyte subsets and their potential influence on intestinal inflammation
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.
Publications
- Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in Crohn disease. J Pediatr Gastroenterol Nutr 2011; 52(5):542-8
Nylund CM, D'Mello S, Kim MO, Bonkowski E, Däbritz J, Foell D, Meddings J, Trapnell BC, Denson LA
- Granulocyte macrophage colony-stimulating factor auto-antibodies and disease relapse in inflammatory bowel disease. Am J Gastroenterol 2013; 108(12):1901-10
Däbritz J, Bonkowski E, Chalk C, Trapnell BC, Langhorst J, Denson LA, Foell D
(See online at https://doi.org/10.1038/ajg.2013.360) - Peripheral monocyte functions and activation in patients with quiescent Crohn’s disease. PLoS ONE 2013; 8(4): e62761
Schwarzmaier D, Foell D, Weinhage T, Varga G, Däbritz J
(See online at https://doi.org/10.1371/journal.pone.0062761) - Granulocyte macrophage-colony stimulating factor and the intestinal innate immune cell homeostasis in Crohn's disease. Am J Physiol Gastrointest Liver Physiol 2014; 306(6):G455-G465
Däbritz J.
(See online at https://doi.org/10.1152/ajpgi.00409.2013) - Granulocyte-macrophage colony stimulating factor autoantibodies and disease relapse in inflammatory bowel disease. US Patent PCT/2014/037927
Däbritz J, Denson LA, Trapnell BC
- Linking immunity, epigenetics and cancer in inflammatory bowel disease. Inflamm Bowel Dis 2014; 20(9):1638-54
Däbritz J & Menheniott TR
(See online at https://doi.org/10.1097/MIB.0000000000000063) - Murine endoscopy for in vivo multimodal imaging of carcinogenesis and assessment of intestinal wound healing and inflammation. J Vis Exp. 2014;(90)
Brückner M, Lenz P, Nowacki TM, Pott F, Foell D, Bettenworth D
(See online at https://doi.org/10.3791/51875) - Granulocyte Macrophage Colony-Stimulating Factor–Activated CD39+/CD73+ Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells. Cell Mol Gastroenterol Hepatol Volume 1, Issue 4, July 2015, Pages 433-449.e1
Weinhage T, Däbritz J, Brockhausen A, Wirth T, Brückner M, Belz M, Foell D, Varga G
(See online at https://doi.org/10.1016/j.jcmgh.2015.04.005) - Immunoregulatory role of myeloid-derived cells in inflammatory bowel disease. Inflammatory Bowel Diseases, Volume 21, Issue 12, 1 December 2015, Pages 2936–2947
Leal MC & Däbritz J
(See online at https://doi.org/10.1097/MIB.0000000000000511) - Reprogramming of monocytes by GM-CSF contributes to regulatory immune functions during intestinal inflammation. J Immunol. 2015 Mar 1;194(5):2424-38
Däbritz J, Weinhage T, Varga G, Wirth T, Walscheid K, Brockhausen A, Schwarzmaier D, Brückner M, Ross M, Bettenworth D, Roth J, Ehrchen JM, Foell D
(See online at https://doi.org/10.4049/jimmunol.1401482) - Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity. Eur J Immunol 2015, 46,8, August 2016, Pages 1997-2007
Däbritz J, Weinhage T, Varga G, Ehrchen J, Wirth T, Barczyk-Kahlert K, Roth J, Schwarz T, Foell D
(See online at https://doi.org/10.1002/eji.201545802)
