Despite recent advances in treatment strategies, infectious diseases are still under
the leading causes of death worldwide. Although the activation of the inflammatory
cascade is one prerequisite of defense, persistent and exuberant immune response,
however, may lead to chronicity of inflammation predisposing to a temporal or permanent
tissue damage not only of the site of infection but also among different body organs.
The initial response to invading pathogens is mediated by the recognition through
various pattern-recognition receptors along with cellular engulfment resulting in a
coordinated release of soluble effector molecules and cytokines aiming to terminate
the external stimuli. Members of the ‘a disintegrin and metalloproteinase’ (ADAM)
family have the capability to proteolytically cleave transmembrane molecules close to
the plasma membrane, a process called ectodomain shedding. In fact, in infectious
diseases dysregulation of numerous ADAM substrates such as junction molecules
(e.g., E-cadherin, VE-cadherin, JAM-A), adhesion molecules (e.g., ICAM-1, VCAM-1,
L-selectin), and chemokines and cytokines (e.g., CXCL16, TNF-α) has been observed.
The alpha-cleavage by ADAM proteases represents a rate limiting step for downstream
regulated intramembrane proteolysis (RIPing) of several substrates, which influence
cellular differentiation, cell signaling pathways and immune modulation. Both the
substrates mentioned above and RIPing crucially contribute to a systematic damage in
cardiovascular, endocrine, and/or gastrointestinal systems. This review will summarize
the current knowledge of ADAM function and the subsequent RIPing in infectious
diseases (e.g., pathogen recognition and clearance) and discuss the potential long-term
effect on pathophysiological changes such as cardiovascular diseases
