OC 58.5 - Cooperation between platelet β1 and β3 integrins in the arrest of bleeding under inflammatory conditions in mice

Tuesday, June 27, 2023

11:45 – 12:00 ET

Room: 515

Session Available As: On-Demand

Presenting Author(s)

Emily Janus-Bell, PhD (she/her/hers)

Post-doc
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France

Co-Author(s)

NR

Nicolas Receveur

Engineer
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
LM

Luc Mercier

Engineer
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
CM

Clarisse Mouriaux

Technician
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
Béatrice Hechler, PhD

Inserm Researcher
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
JR

Jochen Reiser

Research Director
Department of Medicine, Rush University Medical Center, Kellogg Building, Suite 1003, Chicago, IL 60612, USA
Chicago, Illinois, United States
Benoît Ho-Tin-Noé, PhD

Research Director
Université de Paris Descartes, INSERM, Hôpital Bichat, UMR-S1148, F-75000 Paris, France
Paris, Ile-de-France, France
PM

Pierre Mangin

Research Director
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France

Background: Platelets prevent bleeding in a variety of inflammatory settings. The platelet adhesion receptors and activation pathways involved in this function have been shown to be context-dependent and functionally redundant. Remarkably, there are situations where platelets recruited to inflammatory sites operate independently of aggregation. The mechanisms underlying firm and stable adhesion of platelets in inflamed microvessels remain incompletely understood.

Aims: To determine the role of β1 and β3 integrins in stable platelet adhesion at inflammatory sites.

Methods: The impact of isolated or combined platelet-specific genetic deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in different models of acute inflammation: cerebral ischemia-reperfusion caused by transient (2 hours) occlusion of the middle cerebral artery (tMCAO), intranasal lipopolysaccharide (LPS)-induced lung inflammation, and the immune complex-based cutaneous reverse passive Arthus reaction (rpA).

Results: Mice with platelet-directed inactivation of Itgb1 (PF4Cre-β1-/-) did not display abnormal bleeding in the models of acute inflammation. In contrast, mice defective for platelet Itgb3 (PF4Cre-β3-/-) had a statistically significant increase in bleeding in the cutaneous rpA and LPS-induced lung inflammation, but not in the tMCAO model. Remarkably, the bleeding phenotype of PF4Cre-β3-/- mice in the cutaneous rpA was exacerbated by the combined deletion of β1 integrins, with the bleeding phenotype of PF4Cre-β1-/-/β3-/-. Intravital microscopy of the cutaneous rpA highlighted a major defect in PF4Cre-β1-/-/β3-/- platelet adhesion to inflamed microvessels. Unlike isolated platelet deficit in β1 or β3 integrins, combined deficiency in platelet β1 and β3 integrins precipitated early hemorrhagic transformation 6 hours after tMCAO. Combined deficiency in platelet β1 and β3 integrins did not worsen bleeding in LPS-induced lung inflammation as compared to single deficiency in platelet β3 integrins.

Conclusion(s): Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situations.

Learning Objectives:

Upon completion, participants will be able to interpret data from inflammatory bleeding models.
Upon completion, participants will be able to describe the role of platelets in inflammatory bleeding.
Upon completion, participants will be able to explain the role of platelet beta1 and beta3 integrins in inflammatory bleeding.