Exploring the Impact of ACE Inhibition in Immunity and Disease

Abstract

Angiotensin-converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and is crucial in the renin-angiotensin-aldosterone system (RAAS) but also implicated in immune regulation. Intrinsic ACE has been detected in several immune cell populations, including macrophages and neutrophils, where its overexpression results in enhanced bactericidal and antitumour responses, independent of angiotensin II. With roles in antigen presentation and inflammation, the impact of ACE inhibitors must be explored to understand how ACE inhibition may impact our ability to clear infections or malignancy, particularly in the wake of the coronavirus (SARS-CoV2) pandemic and as antibiotic resistance grows. Patients using ACE inhibitors may be more at risk of postsurgical complications as ACE inhibition in human neutrophils results in decreased ROS and phagocytosis whilst angiotensin receptor blockers (ARBs) have no effect. In contrast, ACE is also elevated in certain autoimmune diseases such as rheumatoid arthritis and lupus, and its inhibition benefits patient outcome where inflammatory immune cells are overactive. Although the ACE autoimmune landscape is changing, some studies have conflicting results and require further input. This review seeks to highlight the need for further research covering ACE inhibitor therapeutics and their potential role in improving autoimmune conditions, cancer, or how they may contribute to immunocompromise during infection and neurodegenerative diseases. Understanding ACE inhibition in immune cells is a developing field that will alter how ACE inhibitors are designed in future and aid in developing therapeutic interventions.

Figure 1

Physiological functions of angiotensin-converting enzyme (ACE). A summary of known or observed functions related to ACE activity in both human and murine models. ACE has been associated with several immune pathways related to clearing infection, primarily observed in murine models with high levels of baseline expression. In diseased states, including autoimmune conditions, ACE is elevated in the serum, but its overexpression also confers resistance to cancer and Alzheimer's disease progression. Local ACE may be involved in cellular growth and development, and ACE inhibition blocks the signalling cascades of important pathways. A lack of ACE results in decreased male fertility in mice. The main function of ACE in the RAAS is the regulation of blood pressure through Ang II-dependent actions, as either a vasopressor or vasodilator.

Figure 2

The roles of Ang II and ACE in innate and adaptive immunity. These functions are mediated through the AT₁ receptor signalling cascade in different immune cell lineages where Ang II is present, but through unknown substrates or signals when ACE is utilised. Notably, most immune-related changes are observed in macrophages and neutrophils with respect to ACE, and there is minimal research regarding adaptive immunity. Abbreviations: mΦ: macrophage, DC: dendritic cell, Th-1,2,17: T helper lymphocytes, Treg: T regulatory lymphocyte.

Figure 3

Schematic of the ACE-mediated cleavage of peptides for MHC Class I and II presentation. During MHC Class I (red arrows) antigen preparation, cytoplasmic proteins are processed into peptide fragments via the proteasome. These peptides can be further processed in the endoplasmic reticulum (ER) via ACE, which provides further alterations for increased specificity and selection by CD8⁺ T lymphocytes. The MHC Class II pathway (blue arrows) is for exogenous and endogenous protein digestion within endosomes and lysosomes. Newly synthesised MHC II associates with the invariant chain within the ER, before shuttling the complex to the endocytic pathway. The invariant chain is trimmed to CLIP which remains bound to MHC Class II. Once in the lysosome, CLIP binds HLA-DM to facilitate peptide binding to MHC Class II. The complex is then directed to the cell surface for antigen presentation to CD4⁺ T lymphocytes.

Figure 4

A summary of immune cellular and cytokine changes with ACE inhibitor administration. Importantly, ACEi treatment results in a significant reduction in proinflammatory cytokine production, but these changes appear to be dose-, host-, and disease-dependent. Captopril and lisinopril have been extensively studied in both mice and human autoimmune models but the mechanisms of action are not well understood.