OC 56.4 - GPVI-activated platelets drive the neutrophil profibrotic function in systemic sclerosis

Tuesday, June 27, 2023

11:30 – 11:45 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Roxane Darbousset, PhD

Instructor in Pediatrics
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States

Co-Author(s)

SB

Spoorthi Balu

Research assistant
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States
BW

Brian Wauford

Research assistant
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States
MT

Marc Todd

Research assistant
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States
PC

Pierre Cunin

Assistant Professor
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States
MC

Margaret H. Chang

Assistant Professor
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States
ED

Eilish Dillon

Research assistant
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA
Boston, Massachusetts, United States
ME

Mehreen Elahee

Post-doctoral research fellow
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA
Boston, Massachusetts, United States
DR

Deepak A. Rao

Assistant Professor of Medicine
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA
Boston, Massachusetts, United States
PN

Peter A. Nigrovic

Professor of Pediatrics
Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Boston, Massachusetts, United States

Background: Systemic sclerosis (SSc, scleroderma) is a complex disease of unknown etiology that manifests as progressive tissue fibrosis leading to loss of function in skin, lung, and other organs. In patients with SSc, both platelets and neutrophils in blood exhibit evidence of ongoing activation. However, the role of either of these cell types in SSc remains poorly defined.

Aims: Here, we investigate the platelet-neutrophil interaction as an axis of disease progression in SSc.

Methods: To study this phenomenon, we employed a murine model of SSc induced by repeated intradermal injection of the reactive oxygen species donor hypochlorous acid (HOCl).

Results: We find that circulating platelets are activated early in disease, followed temporally by activation of circulating neutrophils that then infiltrate into fibrosing skin and lung. Depletion of platelets reduces neutrophil activation and depletion of either platelets or neutrophils attenuates fibrosis. Adoptive transfer experiments show that injection of HOCl-SSc neutrophils or healthy neutrophils stimulated with HOCl-SSc platelets leads to fibrosis into healthy mice, which is not the case when PBS neutrophils or healthy neutrophils stimulated with PBS platelets were injected. We further identify that platelet activation is mediated through the collagen receptor GPVI, since mice lacking this receptor exhibit reduced activation of platelets and neutrophils as well as reduced fibrosis. Activated SSc neutrophils isolated from SSc mice and patients exhibit an enhanced capacity to produce NETs, an effector mechanism replicated in healthy neutrophils by GPVI-activated platelets, providing a potential effector mechanism for accelerated fibrosis.

Conclusion(s): Together these studies define a platelet-neutrophil-fibrosis axis in scleroderma, while implicating both GPVI and NETs as candidate therapeutic targets.

Learning Objectives:

Upon completion, participant will be able to define the role of platelets and neutrophlis in scleroderma.
Upon completion, participant will be able to increase their knowledge in auto-immune diseases.
Upon completion, participant will be able to explore potential new therapeutic approaches in the treatment of scleroderma.