Abstract
Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.
Highlights
Proteases of the a disintegrin and metalloproteinase (ADAM)-family play a key role in many physiological and pathological processes during development, inflammation and cancer [1,2]
ADAM17 undergoes maturation by furin-like proteases in the Golgi and can be transported to the cell surface, where the shedding process would occur. This trafficking of ADAM17 mainly depends on iRhom2, since these cells only express iRhom2 but not iRhom1, which is present in most other cells [6,9,10]
We provide multiple lines of evidence that physiologic expression of ADAM17 in phagocytes attenuates bacterial uptake
Summary
Proteases of the a disintegrin and metalloproteinase (ADAM)-family play a key role in many physiological and pathological processes during development, inflammation and cancer [1,2]. ADAM17 undergoes maturation by furin-like proteases in the Golgi and can be transported to the cell surface, where the shedding process would occur. In immune cells, this trafficking of ADAM17 mainly depends on iRhom, since these cells only express iRhom but not iRhom, which is present in most other cells [6,9,10]. Mutations leading to inactivation or hyperactivation of ADAM17 or iRhom in humans are extremely rare Those patients can survive but suffer from recurrent infections or tylosis with oesophageal cancer, highlighting the importance of the iRhom2/ADAM17 axis in immunity, host defence and cancer [11,12,13]. The enhanced bacterial phagocytosis after knockdown of ADAM17 can be reduced by infliximab and etanercept indicating that this is partially dependent on TNFα-signalling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
