Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome that occurs in patients with underlying rheumatic diseases. Preclinical and clinical data suggest that interferon-γ (IFNγ) is pathogenic in MAS, but how IFNγ may be linked to disease pathogenesis remains unknown. This study was undertaken to determine whether IFNγ signals synergize with systemic innate immune responses to drive the cytokine storm in a murine model of MAS.
IFNγ-deficient mice were treated with 5 doses of the Toll-like receptor 9 (TLR-9) agonist CpG 1826, IFNγ, or a combination of the 2 stimuli over the course of 10 days. Immunopathologic features of MAS, including cytopenias, hepatitis, hepatosplenomegaly, and induction of inflammatory myelopoiesis, were assessed. Mixed bone marrow chimeras were created to determine whether TLR-9- and IFNγ receptor 1 (IFNγR1)-dependent signals induce enhanced myelopoiesis in a cell-intrinsic or cell-extrinsic manner.
IFNγ-deficient mice did not develop features of MAS when treated with repeated doses of either the TLR-9 agonist or IFNγ alone. In contrast, IFNγ-deficient mice treated with both the TLR-9 agonist and IFNγ developed cytopenias, hepatitis, and hepatosplenomegaly, reproducing major clinical features of MAS. TLR-9- and IFNγR1-dependent signals synergized to enhance myeloid progenitor cell function and induce myelopoiesis in vivo, which occurred through cell-extrinsic mechanisms and correlated with the induction of disease.
These findings demonstrate that TLR-9-driven signals potentiate the effects of IFNγ to initiate murine MAS, and provide evidence that induction of inflammatory myelopoiesis is a common TLR-9- and IFNγ-dependent pathway that may contribute to the pathogenesis of MAS.