Targeting GM-CSF–IRF5 signaling pathway ameliorates TLR7 overexpression-induced macrophage activation syndrome 3809

Abstract Description Background Macrophage activation syndrome (MAS) is a severe inflammatory condition often associated with autoimmune diseases like systemic juvenile idiopathic arthritis (sJIA). It involves excessive macrophage activation, tissue damage, multi-organ failure, and dysregulated blood cell production. Elevated GM-CSF and IRF5 in TLR7.1 mice were observed, this led us to explore the role of GM-CSF-IRF5 signaling in TLR7-driven MAS. Methods Irf5-/- and GM-CSF-/- mice were treated with topical R848, Ly6Chimonocytes and inflammatory hemophagocytes (iHPCs) in bone marrow, blood, and spleen were analyzed by FC. The TLR7.1 MAS model was used to assess the role of GM-CSF and IRF5 in disease severity. GM-CSF, IL-12, IL-6, and TNFα were measured in TLR7.1, TLR7.1-GM-CSF-/-, and TLR7.1-Irf5-/- mice using LegendPlex. Results Topical R848 treatment in wild-type mice mimics TLR7.1 mice by increasing GM-CSF levels, which upregulate IRF5 expression. This leads to the expansion of Ly6Chimonocytes and iHPCs, causing dysregulated hematopoiesis and anemia. In GM-CSF- or Irf5-deficient TLR7-driven mice, Ly6Chimonocytes and iHPCs were reduced, restoring normal hematopoiesis and preventing MAS. Conclusion TLR7 overexpression causes excessive GM-CSF production, driving IRF5 expression and expansion of Ly6Chimonocytes, which differentiate into iHPCs, contributing to anemia and inflammation in MAS. Targeting GM-CSF or IRF5 may provide therapeutic options for MAS and related autoimmune diseases. Topic Categories Basic Autoimmunity (BA)