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Nrf2 Deficiency in Dendritic Cells Enhances the Adjuvant Effect of Ambient Ultrafine Particles on Allergic Sensitization
Citation:
Li, N., M. Wang, B. Baragas, M. A. WILLIAMS, AND A. E. Nel. Nrf2 Deficiency in Dendritic Cells Enhances the Adjuvant Effect of Ambient Ultrafine Particles on Allergic Sensitization. Herwald H. (Lund), Egestrn A. (Lund) (ed.), Journal of Innate Immunity. Karger Libri AG, Basel, Switzerland, 5(6):543-54, (2013).
Impact/Purpose:
This product represents a collaboration between myself and the group of Dr Andre Nel at UCLA, CA. The major observations of this paper are that 1) ambient ultra fine particulate matter can behave as an immune adjuvant by promoting allergic sensitization and inflammation in a mouse model that involved activation of the dendritic cell (DC) and 2) deficiency of a key anti-oxidant transcription factor called Nrt2 in DC, may promote a constitutive pro-Th2-mediated inflammatory cytokine milieu which we propose may have contributed to the augmentation of the adiuvant effect of UPM on allergic sensitization.
Description:
Airborne particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM-associated chemicals is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II enzymes and is essential in protecting against oxidative stress and lung inflammation. We have prevously shown that traffic-related ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to experimental allergen ovalbumin (OVA) in mice. In the immune system Nrf2 deficiency may interfere with dendritic cell (DC) function and alter their response to UFP. We hypothesized that absence of functional Nrf2 in DC could enhance the immune adjuvant potential of ambient UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2-/-mice compared with their Nrf2+/+ wild-type counterparts. Under resting conditions Nrf2-/- DC displayed an intrinsic predilection to a Th2-polarizing cytokine response characterized by low levels of IL12p70 and high levels of IL-6 secretion as compared Nrf2+/+ DC. UFP induced expression of cell surface-associated functional molecules on Nrf2-/- DC while maintaining the same cytokine pattern. We also demonstrate that allergic sensitization by adoptive transfer of OVA/UFP-treated Nrf2-/- DC provoked a more severe allergic inflammation in the lung than mice sensitized by Nrf2+/+ DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive pro-Th2-mediated inflammatory cytokine milieu, which we propose may have contributed to the augmentation of the adjuvant effect of UFP on allergic sensitization.