Investigating the Role of Nrf2 in Cellular Homeostasis and Interferon Response in Dendritic Cell Exposed to Plasmodium Infected Red Blood Cell

Abstract

Sustaining cellular balance during the immune responses to malaria is crucial for preventing excessive inflammatory damage. Previous work in our laboratory suggests the transcription factor Nrf2 plays an important role in regulating excessive immune activation via effects on Dendritic cells (DC).While Nrf2 serves as a principal regulator of antioxidant defence systems and mitochondrial quality control, its role in DC response to malaria parasites remains poorly understood. We investigated the effects of Nrf2 activity on DC viability, activation, and immunoregulation using murine bone marrow–derived DCs stimulated with Plasmodium-infected red blood cells (iRBCs) in the presence or absence of STING agonist. RNA sequencing analysis showed that iRBC treatment induced interferon-stimulated gene programs (ISGs), encompassing Stat1, Irf1, and Cxcl9. Flow cytometry revealed that cell activation was likely driven primarily by iRBC exposure, while STING served as a secondary amplifier. When Nrf2 was constitutively active, this resulted in suppression of surface activation markers, indicating Nrf2 provides a strong immunoregulatory effect. Cell viability was preserved in Nrf2-active DCs under all stimulation conditions. that iRBCs act as a primary activator of DCs through inflammatory gene induction and co-stimulatory molecule expression, whereas Nrf2 constrains these processes to preserve homeostasis. While this regulatory mechanism may help prevent excessive inflammation, it may also limit the immunogenic potential of DCs, potentially affecting T cell priming and parasite clearance. By linking redox regulation to innate immune sensing in the context of malaria, this work identifies Nrf2 as a key modulator of the balance between immune activation and homeostasis, with potential implications for disease outcome and therapeutic intervention