Exploring the Impact of ACE Inhibition in Immunity and Disease

Figures

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  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.

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  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.

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  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.

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  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.