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
