Science Translational Medicine | 2021
An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo
Abstract
ACE inhibitor treatment reduces human and mouse neutrophil function. An ACE in the hole for bacteria Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) are used by millions of people, including those susceptible to infection, to regulate blood pressure. ACE expression has also been associated with proper function of myeloid cells and neutrophils, but it is unclear how ACEI treatment affects cells of the immune system. Here, Cao et al. demonstrated that ACEI treatment inhibits bactericidal activity by both human and murine neutrophils. ACEI-treated mice or mice lacking ACE expression produced less leukotriene B4, which resulted in poor neutrophil survival. These data suggest that ACEI treatment may increase susceptibility to bacterial infections. Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.