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Semin Thromb Hemost 2018; 44(02): 167-175
DOI: 10.1055/s-0037-1608910
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Immunoregulatory Activities of Activated Protein C in Inflammatory Disease

Cormac J. McDonnell   *
1   Department of Molecular and Cellular Therapeutics, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
,
Erin E. Soule   *
1   Department of Molecular and Cellular Therapeutics, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
,
Patrick T. Walsh
2   Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland
3   National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
,
James S. O'Donnell
1   Department of Molecular and Cellular Therapeutics, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
,
Roger J. S. Preston
1   Department of Molecular and Cellular Therapeutics, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
› Author Affiliations
Further Information

Publication History

Publication Date:
12 December 2017 (online)

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Abstract

Tissue injury prompts the initiation of host defense responses to limit blood loss, restrict pathogen entry, and promote repair. Biochemical and cellular pathways that lead to blood coagulation serve a fundamental role in generating a physical barrier at the wound site, but have also evolved to promote immune response to injury. Similarly, anticoagulant pathways that attenuate clot formation also regulate innate and adaptive immune responses. Of particular importance is activated protein C (APC) which serves as a principal regulator of thrombin generation, shapes the innate immune response to infection, and has been shown to contribute to the adaptive immune response in several preclinical models of autoimmune disease. APC controls blood coagulation by proteolytic degradation of procoagulant activated cofactors essential for fibrin clot development, but also cleaves multiple additional substrates and interacts with cell surface receptors to exert additional physiologically important roles. In this review, we focus on the molecular mechanisms utilized by APC to limit inflammation and, in particular, current understanding of the basis for APC anticoagulant and signaling activities. In particular, we provide an overview of established and emerging signaling pathways initiated by APC on endothelial cells, monocytes, neutrophils, dendritic cells, and T cells to control and regulate immune cell physiology. Finally, we consider the impact of APC activity in the context of both acute and chronic inflammatory disease, and the continuing efforts to harness the immunoregulatory properties of recombinant APC for therapeutic use.

Keywords

activated protein C - monocytes - neutrophils - cell signaling - T cells

* Cormac McDonnell and Erin Soule as cofirst authors contributed equally to the article.


 

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