Donor macrophage pyroptosis contributes to the development of aGVHD

Area of Science:

• Immunology
• Cell Biology
• Transplantation Medicine

Background:

• Pyroptosis, a form of programmed cell death, is implicated in inflammatory diseases.
• Macrophage dysfunction was previously noted in acute graft-versus-host disease (aGVHD).
• The role of pyroptosis in macrophages during aGVHD was previously unknown.

Purpose of the Study:

• To investigate whether macrophages undergo pyroptosis in aGVHD.
• To determine the role of macrophage pyroptosis in aGVHD pathogenesis.
• To explore potential therapeutic strategies targeting pyroptosis in aGVHD.

Main Methods:

• Observation of macrophage pyroptosis in aGVHD mouse models.
• Measurement of serum IL-1β and IL-18 levels in aGVHD patients.
• Analysis of T cell populations (CD69+CD4+ T cells, Th1, Th17, Tregs) in recipient mice.
• Administration of a pyroptosis inhibitor (disulfiram) to assess its therapeutic effects.

Main Results:

• Macrophage pyroptosis was confirmed in aGVHD mice, with increased serum IL-1β and IL-18 in patients.
• Donor-derived macrophages were the primary source of pyroptosis in aGVHD.
• Suppression of pyroptosis in donor macrophages reduced pathological damage and improved survival in aGVHD mice.
• Pyroptosis inhibition modulated CD4+ T cell differentiation and alleviated aGVHD severity without compromising graft-versus-lymphoma (GVL) effects.

Conclusions:

• Donor-derived macrophages undergo pyroptosis during aGVHD, contributing to disease development.
• Macrophage pyroptosis influences CD4+ T cell activation and differentiation in aGVHD.
• The pyroptosis inhibitor disulfiram shows promise as a therapeutic agent for aGVHD, preserving GVL activity.