Role of angiotensin-converting enzyme in myeloid cell immune responses

Abstract

Angiotensin-converting enzyme (ACE), a dicarboxypeptidase, plays a major role in the regulation of blood pressure by cleaving angiotensin I into angiotensin II (Ang II), a potent vasoconstrictor. Because of its wide substrate specificity and tissue distribution, ACE affects many diverse biological processes. In inflammatory diseases, including granuloma, atherosclerosis, chronic kidney disease and bacterial infection, ACE expression gets upregulated in immune cells, especially in myeloid cells. With increasing evidences connecting ACE functions to the pathogenesis of these acquired diseases, it is suggested that ACE plays a vital role in immune functions. Recent studies with mouse models of bacterial infection and tumor suggest that ACE plays an important role in the immune responses of myeloid cells. Inhibition of ACE suppresses neutrophil immune response to bacterial infection. In contrast, ACE overexpression in myeloid cells strongly induced bacterial and tumor resistance in mice. A detailed biochemical understanding of how ACE activates myeloid cells and which ACE peptide(s) (substrate or product) mediate these effects could lead to the development of novel therapies for boosting immunity against a variety of stimuli, including bacterial infection and tumor.

Keywords: Angiotensin-converting enzyme; Dendritic cells; Hematopoiesis; Immune response; MHC class I antigen presentation; Macrophages; Melanoma; Methicillin-resistant Staphylococcus aureus (MRSA); Myeloid cells; Neutrophils.

Fig. 1

ACE upregulation enhances myeloid cell immune responses. In physiological conditions, ACE expression increased during the differentiation and functional maturation of myeloid-derived cells. Upon immune challenge, the expression of ACE further increased in activated myeloid cells facilitated the optimal immune responses of these cells. Upregulation of ACE in myeloid cells (eg. NeuACE neutrophils and ACE10/10 macrophages) strongly enhanced immune responses of these cells, beyond the normal capacity of WT cells. In neutrophils, ACE upregulation induced oxidative bactericidal response, which is due the upregulation of NADPH oxidase activity. In macrophages, ACE upregulation enhanced M1 activation of macrophages due to the increased activation of NF-kB, STAT1 and TNFα, which in turn gives a strong anti-bacterial and anti-tumor phenotype. In APCs (DCs and macrophages), ACE trims the peptide repertoire before they are bound to MHC class I complex and displayed by cells, which activates T cell – adaptive immune response and humoral immune response

Fig. 2

ACE affects anti-bacterial defense. In mice, ACE knockout suppressed bacterial resistance. Representative images showing MRSA skin lesion at day 4 post-bacterial subcutaneous injection (1 × 10⁷ CFU/mouse flank) [Cao D-Y et al. Unpublished data]

Fig. 3

Melanoma tumor growth. In mice, overexpression of ACE C-domain enhanced macrophage anti-tumor activity. Representative images showing tumor growth at day 14 after intradermal injection of B16-F10 melanoma cells (10⁶ cells/mouse) [Cao D-Y et al. Unpublished data]