Angiotensin-converting enzyme in innate and adaptive immunity

Key Points Angiotensin-converting enzyme (ACE) expression by myeloid cells is increased in response to infection. Forced ACE overexpression in mouse macrophages increases their ability to respond to infection and some tumour models, which is in part mediated by increased levels of nitric oxide, superoxide (O 2 − ) and pro-inflammatory cytokines. Forced ACE overexpression in neutrophils increases their response to infection by increasing NADPH oxidase-dependent production of O 2 − . The effects of ACE overexpression are not mediated by angiotensin II, any other angiotensin peptides or the type 1 angiotensin II receptor but instead by unknown ACE substrate(s) or product(s). No known immunological framework can currently explain the effects of ACE overexpression, but an as yet unrecognized pathway capable of stimulating myeloid function beyond levels achievable by wild-type cells must exist. Angiotensin-converting enzyme (ACE) not only plays a major part in the regulation of blood pressure but also participates in several other physiological functions, including renal development and male reproduction. Here, Bernstein et al. discuss how ACE enhances both innate and adaptive responses by modulating macrophage and neutrophil function. Angiotensin-converting enzyme (ACE) — a zinc-dependent dicarboxypeptidase with two catalytic domains — plays a major part in blood pressure regulation by converting angiotensin I to angiotensin II. However, ACE cleaves many peptides besides angiotensin I and thereby affects diverse physiological functions, including renal development and male reproduction. In addition, ACE has a role in both innate and adaptive responses by modulating macrophage and neutrophil function — effects that are magnified when these cells overexpress ACE. Macrophages that overexpress ACE are more effective against tumours and infections. Neutrophils that overexpress ACE have an increased production of superoxide, which increases their ability to kill bacteria. These effects are due to increased ACE activity but are independent of angiotensin II. ACE also affects the display of major histocompatibility complex (MHC) class I and MHC class II peptides, potentially by enzymatically trimming these peptides. Understanding how ACE expression and activity affect myeloid cells may hold great promise for therapeutic manipulation, including the treatment of both infection and malignancy.