The protective role of transcription factor Nrf2 in murine macrophage activation syndrome

Macrophage activation syndrome (MAS) is characterized by multilineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 is a master regulator of redox homeostasis. In this work, we aim to investigate the role of Nrf2 in murine hyperinflammation and the mechanisms by which Nrf2 activation by red blood cell products regulates proinflammatory cytokine production.

We induced murine MAS in wild-type and Nrf2 knockout (Nrf2-/-) mice by repeat administration of TLR9-agonist CpG. Clinical and biochemical markers of disease were measured including complete blood counts, liver and spleen pathology, serum free heme, ferritin, and cytokine profiles. In vitro bone marrow-derived macrophages and dendritic cells were used to investigate regulation of CpG-induced cytokine expression by oxidized red blood cells and hemin.

Patients with hyperinflammatory disease had higher levels of Nrf2 gene expression. Mice with CpG-induced hyperinflammation had elevated systemic lipid peroxidation, which was exacerbated in Nrf2-/- mice. Compared with wild-type control mice, Nrf2-/- mice developed significantly worse organomegaly, organ pathology, and reticulocytosis. Nrf2-/- mice had exacerbated hypercytokinemia in cytokines central MAS physiology: interleukin (IL)-12, interferon γ, and IL-10. In vitro, we found that oxidized red blood cell lysates and hemin were able to suppress IL-12 transcription and protein production from bone marrow-derived dendritic cells in an Nrf2-dependent manner.

Together, our findings show that transcription factor Nrf2 is highly expressed in patients with hyperinflammatory disease and demonstrate a protective role for Nrf2 in a murine model of MAS in part due to Nrf2-mediated suppression of proinflammatory cytokine production.