An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo

Abstract

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.

CCL28 modulates neutrophil responses during infection with mucosal pathogens

“…After enrichment, 2.5 x 10 6 cells/mL were resuspended in phenol red-free RPMI media (Gibco) supplemented with 10% FBS (Gibco), and HEPES (1mM, Invitrogen). The cells were incubated in presence of 2’,7’-dichlorodihydrofluorescein diacetate (H 2 DCFDA, 25 mM) (Invitrogen) for 30min at 37 °C and 5% of CO 2 , as previously described (62). After incubation with H 2 DCFDA, neutrophils were infected with STm as described above, then incubated for 4h with mouse recombinant CCL28 (50 nM), anti-mouse CCR3 antibody (5 mg/1×10 6 cells, clone 83103), anti-mouse CCR10 antibody (5 mg/1×10 6 cells, clone 248918) or anti-rat IgG2A (5 mg/1×10 6 cells, clone 54447), all from R&D Systems.…”

Exploring the Impact of ACE Inhibition in Immunity and Disease

“…Human and animal studies are crucial to our understanding and management of hypertensive patients with underlying conditions or complications that may be exacerbated by medications, particularly immunocompromised individuals with increased susceptibility to infection. In human neutrophils, some ACE inhibitors and ARBs are able to negatively affect cellular antimicrobial responses particularly extracellular and intracellular clearing of bacterial invaders [ 48 ]. In other immune cells, very little is known of how well they take up these drugs, and if their phagocytic or bactericidal abilities are impacted by them.…”

“…During bacterial infection, ACE is integral in antigen presentation and in clearing the infection [ 23 , 24 ]. Neutrophils treated with ramipril or lisinopril had a decreased ability to clear MRSA infection in a human pilot study, whilst ARBs had no significant effect [ 48 ]. The p38-MAPK pathway and leukotriene B4 (LTB 4 ) activity have been highlighted as important factors in ROS, chemotaxis, and cytokine production in neutrophils.…”

“…LTB 4 acts in neutrophil adhesion or extravasation into sites of inflammation or infection, and neutrophils are unable to function properly and have reduced survival if its expression is reduced or inactivated [ 48 , 125 ]. Given that lisinopril and ramipril treatment showed decreased neutrophil bactericidal ability, it is postulated that ACE inhibition reduces their antimicrobial impact through reduced LTB 4 production [ 48 ]. ACE expression also altered LTB 4 production and could be ameliorated with LTB 4 inhibition, resulting in reduced MRSA clearance in transgenic mice and human neutrophils [ 48 ].…”

“…Given that lisinopril and ramipril treatment showed decreased neutrophil bactericidal ability, it is postulated that ACE inhibition reduces their antimicrobial impact through reduced LTB 4 production [ 48 ]. ACE expression also altered LTB 4 production and could be ameliorated with LTB 4 inhibition, resulting in reduced MRSA clearance in transgenic mice and human neutrophils [ 48 ]. LTA 4 hydrolase metabolizes LTA 4 into LTB 4 through the 5-lipoxygenase pathway [ 126 , 127 ].…”