Toll-like receptor 9 activation potentiates interferon-γ-mediated immunopathology in a murine model of Macrophage Activation Syndrome.

OBJECTIVE: Macrophage Activation Syndrome (MAS) is a life-threatening cytokine storm syndrome that occurs in patients with underlying rheumatologic diseases. Preclinical and clinical data suggest that interferon (IFN)γ is pathogenic in MAS, yet how IFNγ causes disease remains unknown. In this manuscript, we sought to determine whether IFNγ-dependent signals synergize with systemic innate immune responses to drive cytokine storm in a murine model of MAS.

METHODS: IFNγ-deficient mice were treated with five doses of a Toll-like receptor (TLR)9 agonist (CpG1826), IFNγ, or a combination of the two stimuli over the course of ten days. MAS immunopathology was assessed by measuring cytopenias, hepatitis, hepatosplenomegaly, and the induction of inflammatory myelopoiesis. Mixed bone marrow chimeras were created to determine if TLR9- and IFNγR1- dependent signals induce enhanced myelopoiesis in a cell-intrinsic or cell-extrinsic manner.

RESULTS: IFNγ-deficient mice do not develop features of MAS when treated with repeated doses of a TLR9 agonist or IFNγ individually. In contrast, IFNγ-deficient mice treated with both a TLR9 agonist and IFNγ develop cytopenias, hepatitis, and hepatosplenomegaly reproducing major clinical features of MAS. TLR9- and IFNγ- dependent signals synergize to enhance myeloid progenitor function and induce myelopoiesis in vivo, which occurs through cell-extrinsic mechanisms and correlates with induction of disease.

CONCLUSION: These data demonstrate that TLR9-driven signals potentiate the effects of IFNγ to initiate murine MAS, and provide evidence that induction of inflammation-induced myelopoiesis is a common TLR- and IFNγ- dependent pathway that may contribute to the pathogenesis of MAS. This article is protected by copyright. All rights reserved.