Nrf2 Deficiency in Dendritic Cells Enhances the Adjuvant Effect of Ambient Ultrafine Particles on Allergic Sensitization

Abstract

Particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM 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 previously shown that ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to ovalbumin (OVA) in mice. We hypothesized that Nrf2 deficiency in dendritic cells (DC) could enhance the adjuvant potential of UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2 knockout (Nrf2^-/-) mice compared with their wild-type (Nrf2^+/+) counterparts. Under resting conditions, Nrf2^-/- DC displayed an intrinsic predilection to a T helper 2-favoring cytokine profile characterized by a low level of IL-12p70 and a high level of IL-6 as compared to Nrf2^+/+ DC. Adoptive transfer of OVA/UFP-treated Nrf2^-/- DC provoked a more severe allergic inflammation in the lung than Nrf2^+/+ DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive immune-polarizing cytokine milieu, which we propose may have contributed to the augmented adjuvant effect of UFP on allergic sensitization.

Fine particulate matter (PM2.5) enhances allergic sensitization in BALB/cmice

“…Because inflammatory effects of PM have been attributed to oxidative stress (Li et al 2008; 2009; 2013), protein expression of HO-1 in lung tissue was determined. Epithelial cells, fibroblasts, and macrophages were positive for HO-1 expression (Figure 5, A-D), especially following OVA/OVA and OVA+PM/OVA treatment.…”

Allergic Airway Inflammation is Differentially Exacerbated by Daytime and Nighttime Ultrafine and Submicron Fine Ambient Particles: Heme Oxygenase-1 as an Indicator of PM-Mediated Allergic Inflammation

“…Further, evidence from in vivo studies utilizing chronic UF ambient particle exposure demonstrated activation of the Nrf-2 signaling pathway, a regulator of HO-1 and a pathway subject to diminished upregulation with aging that might potentially explain additional susceptibility in the aging population to PM pollution (Zhang et al, 2012). To this point, Li et al (2013) recently demonstrated that adoptive transfer of dendritic cells exposed to UF particles with allergen resulted in a more severe allergic response in Nrf-2 −/-dendritic cells than for Nrf-2 +/+ . Taken together with the findings from this study, the data suggest that further research into Nrf-2 mediated HO-1 activity and induction may be critical to understanding the ability of particles to worsen allergic airway inflammation.…”

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

“…While this does not preclude Nrf2 from having a role during sensitization, these data indicate that Nrf2-mediated reduction in asthma occurs at the challenge phase, which may be due to acute cytoprotective responses. Other studies demonstrate that Nrf2 alters dendritic cell function and skews the Th2 response (29,57), suggesting that Nrf2 may also function during sensitization. We explored the role of Nrf2 in airway epithelial cell function, which is an important component of asthma susceptibility, and we showed that Nrf2 has a strong protective role in the airway epithelium of sensitized and challenged mice.…”

“…Additionally, dendritic cells from Nrf2-deficient mice display enhanced surface expression of activation markers, increased oxidative stress, and heightened Th2 responses, compared with dendritic cells from wild-type mice after ex vivo stimulation with allergen (29,40,57). Furthermore, Nrf2 protein levels and Nrf2-regulated antioxidant responses are markedly reduced in airway smooth muscle cells from severe asthmatic subjects, compared with normal subjects, suggesting that the Nrf2 response may be impaired in asthmatic subjects (32).…”