The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation

Salamah, M. F., Ravishankar, D., Kodji, X., Moraes, L. A., Williams, H. F., Vallance, T. M., Albadawi, D. A., Vaiyapuri, R., Watson, K. ORCID: https://orcid.org/0000-0002-9987-8539, Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352, Brain, S. D., Perretti, M. and Vaiyapuri, S. ORCID: https://orcid.org/0000-0002-6006-6517 (2018) The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation. Blood Advances, 2 (21). pp. 2973-2985. ISSN 2473-9529 doi: 10.1182/bloodadvances.2018021758

Abstract/Summary

Platelet-associated complications including thrombosis, thrombocytopenia and haemorrhage are commonly observed during various inflammatory diseases such as psoriasis, sepsis and inflammatory bowel disease. Despite the reported evidence on numerous mechanisms/molecules that may contribute to the dysfunction of platelets, the primary mechanisms that underpin platelet-associated complications during inflammatory diseases are not fully established. Here, we report the discovery of formyl peptide receptor 2, FPR2/ALX in platelets, and its primary role in the development of platelet-associated complications via ligation with its ligand, LL37. LL37 acts as a powerful endogenous antimicrobial peptide but it also regulates innate immune responses. We demonstrate the impact of LL37 in the modulation of platelet reactivity, haemostasis, and thrombosis. LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail bleeding time in mice. By utilising a pharmacological inhibitor and Fpr2/3 (an orthologue of human FPR2/ALX)-deficient mice, the functional dependence of LL37 on FPR2/ALX was determined. Since the level of LL37 is increased in numerous inflammatory diseases, these results point towards a critical role for LL37 and FPR2/ALX in the development of platelet-related complications in such diseases. Hence, a better understanding of the clinical relevance of LL37 and FPR2/ALX in diverse pathophysiological settings will pave the way for the development of improved therapeutic strategies for a range of thromboinflammatory diseases.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/79972
Item Type	Article
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) > Mass Spectrometry (CAF) University of Reading Malaysia Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	American Society of Hematology
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