The Ribonuclease A Superfamily in Humans: Canonical RNases as the Buttress of Innate Immunity

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Abstract

In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding of these proteins’ physiological roles is lacking. Different biological effects can be attributed to each protein, including antiviral, antibacterial and antifungal activities as well as cytotoxic effects against host cells and parasites. Different immunomodulatory effects have also been demonstrated. This review summarizes the available data on the human RNase A superfamily and illustrates the significant role of the eight canonical RNases in inflammation and the host defence system against infections.

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Eosinophils: changing perspectives in health and disease

Helene F. Rosenberg, Kimberly D Dyer, Paul Foster (2012)

Key Points Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have provided a more sophisticated understanding of eosinophil effector functions and a more nuanced view of their contributions to the pathogenesis of various diseases, including asthma and respiratory allergies, eosinophilic gastrointestinal diseases, hypereosinophilic syndromes and parasitic infection. Eosinophils are granulocytes that develop in the bone marrow from pluripotent progenitors in response to cytokines, such as interleukin-5 (IL-5), IL-3 and granulocyte–macrophage colony-stimulating factor (GM-CSF). Mature eosinophils are released into the peripheral blood and enter tissues in response to cooperative signalling between IL-5 and eotaxin family chemokines. Eosinophils in peripheral blood and tissues are uniquely identified by their bilobed nuclei, their large specific granules that store cytokines, cationic proteins and enzymes, and their expression of the IL-5 receptor and CC-chemokine receptor 3 (CCR3). In addition, the receptors sialic acid-binding immunoglobulin-like lectin 8 (SIGLEC-8) and SIGLEC-F are expressed by human and mouse eosinophils, respectively. IL-5 has a central and profound role in all aspects of eosinophil development, activation and survival. IL-5 is produced by T helper 2 (TH2) cells, and more recently the contributions of the epithelium-derived innate cytokines thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 in promoting eosinophilia via the induction of IL-5 have also been recognized. Although eosinophil responses are influenced by cytokines produced by T cells, eosinophils in turn modulate the functions of B and T cells. Eosinophils also communicate with a range of innate immune cells (such as mast cells, dendritic cells, macrophages and neutrophils). Eosinophils serve to bridge innate and adaptive immunity by regulating the production of chemoattractants and cytokines (including CC-chemokine ligand 17 (CCL17), CCL22, a proliferation-inducing ligand (APRIL) and IL-6) and via antigen presentation. Both successful and unsuccessful attempts to target eosinophils have yielded remarkable insights into their contribution to disease pathogenesis. Many eosinophil-associated inflammatory conditions have been shown to be heterogeneous in nature. As such, successful therapeutic strategies will depend on the correlation of disease activity with dysregulated eosinophil function as well as the identification of the crucial molecules that regulate eosinophil accumulation in the affected tissues. Supplementary information The online version of this article (doi:10.1038/nri3341) contains supplementary material, which is available to authorized users.

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Angiogenins: a new class of microbicidal proteins involved in innate immunity.

Lora Hooper, Thaddeus S. Stappenbeck, Chieu Hong … (2003)

Although angiogenins have been implicated in tumor-associated angiogenesis, their normal physiologic function remains unclear. We show that a previously uncharacterized angiogenin, Ang4, is produced by mouse Paneth cells, is secreted into the gut lumen and has bactericidal activity against intestinal microbes. Ang4 expression is induced by Bacteroides thetaiotaomicron, a predominant member of the gut microflora, revealing a mechanism whereby intestinal commensal bacteria influence gut microbial ecology and shape innate immunity. Furthermore, mouse Ang1 and human angiogenin, circulating proteins induced during inflammation, exhibit microbicidal activity against systemic bacterial and fungal pathogens, suggesting that they contribute to systemic responses to infection. These results establish angiogenins as a family of endogenous antimicrobial proteins.

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Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.

C Kannemeier, A Shibamiya, F Nakazawa … (2007)

Upon vascular injury, locally controlled haemostasis prevents life-threatening blood loss and ensures wound healing. Intracellular material derived from damaged cells at these sites will become exposed to blood components and could contribute to blood coagulation and pathological thrombus formation. So far, the functional and mechanistic consequences of this concept are not understood. Here, we present in vivo and in vitro evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation. Extracellular RNA was found to augment (auto-)activation of proteases of the contact phase pathway of blood coagulation such as factors XII and XI, both exhibiting strong RNA binding. Moreover, administration of exogenous RNA provoked a significant procoagulant response in rabbits. In mice that underwent an arterial thrombosis model, extracellular RNA was found associated with fibrin-rich thrombi, and pretreatment with RNase (but not DNase) significantly delayed occlusive thrombus formation. Thus, extracellular RNA derived from damaged or necrotic cells particularly under pathological conditions or severe tissue damage represents the long sought natural "foreign surface" and provides a procoagulant cofactor template for the factors XII/XI-induced contact activation/amplification of blood coagulation. Extracellular RNA thereby reveals a yet unrecognized target for antithrombotic intervention, using RNase or related therapeutic strategies.

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Author and article information

Contributors

Ester Boix: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 05 August 2016

Publication date Collection: August 2016

Volume: 17

Issue: 8

Electronic Location Identifier: 1278

Affiliations

[1 ]Department of Intensive Care and Intermediate Care, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany; pkoczera@ 123456ukaachen.de (P.K.); lmartin@ 123456ukaachen.de (L.M.); gmarx@ 123456ukaachen.de (G.M.)

[2 ]Department for Experimental Molecular Imaging, University Hospital RWTH Aachen and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen 52074, Germany

Author notes

[* ]Correspondence: tschuerholz@ 123456ukaachen.de ; Tel.: +49-241-80-35871

Article

Publisher ID: ijms-17-01278

DOI: 10.3390/ijms17081278

PMC ID: 5000675

PubMed ID: 27527162

SO-VID: 9d56dc13-1a43-4bf6-b68d-910f807ef24f

License:

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 11 May 2016

Date accepted : 01 August 2016

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The Ribonuclease A Superfamily in Humans: Canonical RNases as the Buttress of Innate Immunity

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Abstract

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Higher order chromatin architecture

Most cited references 114

Eosinophils: changing perspectives in health and disease

Angiogenins: a new class of microbicidal proteins involved in innate immunity.

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.

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Cited by 57

Most referenced authors 2,506