Angiotensin-converting enzyme in innate and adaptive immunity

Abstract

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.

Figure 1 |. Functional diversity of ACE.

Angiotensin-converting enzyme (ACE) has several peptide substrates, which are involved in multiple physiological functions. The production of the vasoconstrictor angiotensin II and the cleavage of the vasodilator bradykinin result in an increase in blood pressure (BP). In humans, a lack of ACE leads to low BP within the fetus and the development of renal tubular dysgenesis. Many immune effects of ACE are independent of angiotensin II, but the peptide substrate(s) and/or product(s) that mediate these effects are currently unknown. So far, ACE is known to inactivate the 4-amino acid peptide acetyl-SDKP, which has been described as an anti-inflammatory molecule. However, as an inhibitor of acetyl-SDKP formation does not affect the neutrophil immune response of wild-type mice, this molecule is unlikely to play a major part in the improved immune response mediated by ACE overexpression. Male germ cells produce testis ACE, an isozyme of ACE, which is smaller than the somatic form, as it contains only the carboxy-terminal domain. Experiments in mice show that males without testis ACE reproduce very poorly. The substrate and product of testis ACE responsible for normal fertility are not known but are almost certainly not angiotensin I or angiotensin II.

Figure 2 |. Macrophage-specific ACE overexpression suppresses tumour growth.

a | ACE 10/10 mice overexpress angiotensin-converting enzyme (ACE) in macrophages. ACE is predominantly located on the cell surface but is also present within the endoplasmic reticulum (ER) and probably within endosomes. b | Analysis of tumour volume 14 days after intradermal implantation of B16-F10 melanoma cells into ACE 10/10 mice, ACE 10/10 mice crossed with ACE wild-type (WT) mice (heterozygous (HZ) mice) and WT mice shows that ACE overexpression in macrophages attenuates tumour growth. Data from individual mice (open blue diamonds) as well as the group means (filled orange circles) and standard error of the mean are shown. c | Representative images of the tumours at day 14 in ACE 10/10 mice and ACE WT mice are presented. Parts b and c are adapted with permission from REF. , Elsevier.

Figure 3 |. ACE participates in peptide trimming during antigen processing.

Angiotensin-converting enzyme (ACE) overexpression in antigen-presenting cells (APCs) likely changes the display of both major histocompatibility (MHC) class I and MHC class II epitopes. MHC class I and MHC class II proteins bind and display peptides on the surface of cells. As a peptidase, ACE can cut peptides and thereby affect the diversity of peptides that are presented to T cells. a | Cytoplasmic proteins are proteolytically cleaved by the proteasome to become potential MHC class I peptides, which are imported into the endoplasmic reticulum (ER) via peptide transporter involved in antigen processing (TAP). ACE helps trim MHC class I peptides within the ER, which occurs in both wild-type and ACE-overexpressing APCs. b | ACE expression also changes MHC class II presentation of peptide epitopes, although the exact subcellular location and mechanism is somewhat unclear. CLIP, class II-associated invariant chain peptide; Ii, invariant chain; MVB, multivesicular body; TCR, T cell receptor.

Figure 4 |. ACE overexpression in neutrophils reduces skin lesions caused by MRSA infection.

a | NeuACE mice overexpress angiotensin-converting enzyme (ACE) in neutrophils, but the enzyme is present in other cell types as well. b | Skin lesion area sizes (and standard error of the mean) of NeuACE and wild-type (WT) mice that were subcutaneously injected with methicillin-resistant Staphylococcus aureus (MRSA) on day 0, including mice that had previously been depleted of neutrophils using anti-neutrophil antibodies. The data show that overexpression of ACE in neutrophils provides resistance against MRSA infection. c | Bacterial numbers within the skin lesions after 3 days in NeuACE and WT mice show that overexpression of ACE in neutrophils attenuates bacterial numbers following MRSA infection. Data from individual mice (open blue diamonds) as well as the group means (orange bars) and standard error of the mean are shown. d | Representative images of NeuACE and WT mice 3 days after infection with MRSA, illustrating the difference in lesion size. *P < 0.001. CFU, colony forming unit; NS, not significant. Parts b–d are republished with permission of American Society of Hematology, from Khan, Z. et al. Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood 130, 328–339 (2017); permission conveyed through Copyright Clearance Center, Inc. (REF. 68).

Figure 5 |. ACE overexpression enhances the adaptive and innate immune response.

a | In ACE 10/10 mice, angiotensin-converting enzyme (ACE) overexpression in monocytes and macrophages enhances the immune response in several ways. Resistance to bacterial infection is increased through elevated production of superoxide (O₂⁻), nitric oxide, tumour necrosis factor (TNF) and IL-12β; resistance to tumour growth is due to direct cytotoxic effects on tumour cells through an enhanced CD8⁺ T cell response and an increase in pro-inflammatory cytokines. In addition, ACE 10/10 mice produce more antibodies than do wild-type animals, presumably owing to an enhanced display of cell surface epitopes that increase the response of CD4⁺ T helper 1 (T_H1) or T_H2 cells, which have a key role in B cell maturation. b | In NeuACE mice, neutrophils overexpress ACE, leading to increased production of O₂⁻ in response to bacterial infection via phosphorylation of p47-PHOX, the regulatory subunit of the NADPH complex. Increased O₂⁻ production improves cytokine and neutrophil extracellular trap (NET) formation. IgG, immunoglobulin-γ; MHC, major histocompatibility complex; TCR, T cell receptor.