Angiotensin-converting enzyme in innate and adaptive immunity

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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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PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

Pingxin Li, Ming‐ming Li, Michael Lindberg … (2010)

Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4+/+ neutrophils, PAD4−/− neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4−/− mice are more susceptible to bacterial infection than PAD4+/+ mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.

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Revisiting the role of the granuloma in tuberculosis.

Lalita Ramakrishnan (2012)

The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries--from imaging studies coupled with genetic manipulations--that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases.

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Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality.

Q Remijsen, T. W. Kuijpers, E Wirawan … (2011)

Neutrophil extracellular traps (NETs) are chromatin structures loaded with antimicrobial molecules. They can trap and kill various bacterial, fungal and protozoal pathogens, and their release is one of the first lines of defense against pathogens. In vivo, NETs are released during a form of pathogen-induced cell death, which was recently named NETosis. Ex vivo, both dead and viable neutrophils can be stimulated to release NETs composed of either nuclear or mitochondrial chromatin, respectively. In certain pathological conditions, NETs are associated with severe tissue damage or certain auto-immune diseases. This review describes the recent progress made in the identification of the mechanisms involved in NETosis and discusses its interplay with autophagy and apoptosis. © 2011 Macmillan Publishers Limited