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Angiotensin-converting enzyme in innate and adaptive immunity

Nature Reviews Nephrology volume 14, pages 325–336 (2018)Cite this article

Subjects

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 (O2−) and pro-inflammatory cytokines.

  • Forced ACE overexpression in neutrophils increases their response to infection by increasing NADPH oxidase-dependent production of O2−.

  • 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.

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.

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Figure 1: Functional diversity of ACE.
Figure 2: Macrophage-specific ACE overexpression suppresses tumour growth.
Figure 3: ACE participates in peptide trimming during antigen processing.
Figure 4: ACE overexpression in neutrophils reduces skin lesions caused by MRSA infection.
Figure 5: ACE overexpression enhances the adaptive and innate immune response.

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Acknowledgements

The authors thank B. Taylor of Cedars-Sinai Medical Center for help in preparing the manuscript before submission. The authors' work described in this Review was supported by US National Institute of Health grants P01HL129941, R21AI114965 and R03DK101592, and American Heart Association grants 16SDG30130015 and 17GRNT33661206.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Cedars-Sinai Medical Center,

    Kenneth E. Bernstein, Zakir Khan, Jorge F. Giani, Duo-Yao Cao & Ellen A. Bernstein

  2. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Kenneth E. Bernstein & Jorge F. Giani

  3. Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China

    Xiao Z. Shen

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All authors substantially contributed to the discussion of the content. K.E.B., Z.K., D.-Y.C. and X.Z.S. researched data for the article. K.E.B., J.F.G., E.A.B. and X.Z.S. drafted and edited the manuscript before submission.

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Supplementary information

Supplementary information S1 (figure)

Angiotensinogen knockout mice were bred such that their ACE genes were either homozygous for the ACE 10 mutation (10/10) or WT for ACE. (PDF 66 kb)

Supplementary information S2 (figure)

A mouse model of Alzheimer's disease was crossed such that the ACE genes were either WT or ACE 10/10. (PDF 1919 kb)

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Glossary

ACE inhibitors

Compounds that block the formation of angiotensin II and all other angiotensin-converting enzyme (ACE) products by inhibiting ACE activity.

Sarcoidosis

A granulomatous disease characterized by abnormal foci of inflammation. This disease is often associated with high plasma levels of angiotensin-converting enzyme.

Type 1 angiotensin II receptors

(AT1Rs). Receptors for angiotensin II that mediate a variety of functions, such as decreased renal blood flow. Whereas humans have a single gene for this receptor (AGTR1), mice have two genes (Agtr1a and Agtr1b), which encode proteins that are referred to as AT1A and AT1B, respectively. Studies in Agtr1a−/− mice have demonstrated that most angiotensin II-mediated effects in the kidney are mediated by AT1A.

ACE-like enzymes

Enzymes that have protein sequence similarity to human or mouse angiotensin-converting enzyme (ACE). Such enzymes usually bind zinc and have two catalytic domains.

Granulomas

Compact aggregates of immune cells in response to infection or another form of chronic stimulation, resulting in a physical barrier surrounding the enclosed bacteria and hindering the spread of the pathogen throughout the organism. Tuberculosis is most commonly associated with granulomas, but a number of other infectious and noninfectious diseases induce granulomas, as do difficult-to-phagocytize inert foreign bodies such as those in berylliosis.

Histoplasmosis

A granulomatous disease, often primary of the lung, caused by the fungus Histoplasma capsulatum.

Leprosy

A granulomatous disease caused by Mycobacterium leprae; also known as Hansen disease.

Silicosis

A granulomatous disease, often primary of the lung, caused by exposure to silica dust.

Granulomatosis with polyangiitis

A systemic form of vasculitis (inflammation of blood vessels) often referred to as Wegener granulomatosis. The vasculitis typically involves small-to-medium-sized blood vessels that become inflamed and can develop granulomas. The origin of the disease is thought to be due to anti-neutrophil cytoplasmic antibodies (ANCAs).

Schistosomiasis

A parasitic infection caused by the flatworm genus Schistosoma. Eggs of these worms can induce a granulomatous inflammatory response.

ACE 10/10 mice

Mice homozygous for the angiotensin-converting enzyme (ACE) 10 mutation, resulting in ACE overexpression in myeloid cells, particularly in monocytes and macrophages. These animals develop normally and have normal blood pressure because ACE present on the surface of monocytes and macrophages, as well as circulating ACE shed from these cells, maintains normal angiotensin II plasma levels.

B16 melanoma

An aggressive mouse tumour cell line that, when implanted into the skin, develops into a 600 mm3 lesion in ∼2 weeks.

Syngeneic mice

Mice that can donate tissue or cells without triggering an immune response in the recipient mice because cellular proteins and the derived cell surface major histocompatibility complex (MHC) class I peptides are identical.

Ovalbumin

(OVA). A main protein found in egg white. OVA is often used in immunology studies, as many reagents are commercially available, and many details are known as to how the protein stimulates an immune response.

NeuACE mice

Mice that have been genetically modified to overexpress angiotensin-converting enzyme (ACE) in neutrophils. Unlike ACE 10/10 mice, NeuACE mice retain normal levels of ACE expression in all other tissues and cells, including lungs, kidneys, monocytes and macrophages. These animals also develop normally and have normal blood pressure.

Anti-neutrophil antisera

Antibodies that recognize and attach to neutrophils, leading to neutrophil depletion.

Amyloid plaques

Extracellular collections of amyloid protein in the brain. Such plaques are typical of Alzheimer disease.

Alzheimer-prone mice

Mice that have been genetically modified to produce mutant versions of amyloid precursor protein and presenilin owing to expression of transgenic APPK595N,M596L and PS1ΔE9. These mice develop amyloid plaques in the brain over time and show a decreased ability to learn new tasks.

Barnes maze test

A test involving a white platform with 20 equally spaced holes. Only one hole leads to an escape box, whereas the other holes lead to boxes that are too small to enter. The mice are trained to enter the escape box over several days. By measuring the time an animal takes to enter the escape box, and by measuring how rapidly knowledge of the location of the escape box is lost over several days, one can estimate learning and memory retention.

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Bernstein, K., Khan, Z., Giani, J. et al. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol 14, 325–336 (2018). https://doi.org/10.1038/nrneph.2018.15

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