Inhaled Birch Pollen Extract Induces Airway Hyperresponsiveness via Oxidative Stress but Independently of Pollen-Intrinsic NADPH Oxidase Activity, or the TLR4–TRIF Pathway

Abstract

Oxidative stress in allergic asthma may result from oxidase activity or pro-inflammatory molecules in pollens. Signaling via TLR4 and its adaptor TRIF has been implicated in reactive oxygen species (ROS)-mediated acute lung injury and in T helper 2 immune responses. We investigated the contributions of oxidative stress and TLR4/TRIF signaling to experimental asthma induced by birch pollen exposure exclusively via the airways. Mice were exposed to native or heat-inactivated white birch pollen extract (BPEx) intratracheally and injected with the antioxidants, N-acetyl-L-cysteine (NAC) or dimethylthiourea (DMTU) prior to sensitization, challenge, or all allergen exposures, to assess the role of oxidative stress and pollen-intrinsic NADPH oxidase activity in allergic sensitization, inflammation and airway hyperresponsiveness (AHR). Additionally, TLR4 signaling was antagonized concomitantly with allergen exposure, or the development of allergic airway disease was evaluated in TLR4 or TRIF knockout mice. NAC inhibited BPEx-induced eosinophilic airway inflammation and AHR except when given exclusively during sensitization, whereas DMTU was inhibitory even when administered with the sensitization alone. Heat-inactivation of BPEx had no effect on the development of allergic airway disease. Oxidative stress-mediated AHR was also TLR4- and TRIF-independent, however, TLR4 deficiency decreased, while TRIF deficiency increased BPEx-induced airway inflammation. In conclusion, oxidative stress plays a significant role in allergic sensitization to pollen via the airway mucosa, but the pollen-intrinsic NADPH oxidase activity and TLR4 or TRIF signaling are unnecessary for the induction of allergic airway disease and AHR. Pollen extract does, however, activate TLR4, thereby enhancing airway inflammation which is restrained by the TRIF-dependent pathway.

Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment

“…In mice sensitized to RWPE, conjunctival challenge with ragweed pollen extract has been reported to stimulate TLR4-dependent allergic inflammation in murine and human corneal epithelia (32). Likewise, another group reported that the adaptive immune response to birch pollen extract was inhibited in mice lacking TLR4 (31). Our data indicate that the TLR4-CXCR2 pathway may have contributed to allergic inflammation in those studies by controlling pollen-induced recruitment of activated neutrophils.…”

“…The role of TLRs in pollen-induced allergic inflammation has been evaluated recently (31,32). In mice sensitized to RWPE, conjunctival challenge with ragweed pollen extract has been reported to stimulate TLR4-dependent allergic inflammation in murine and human corneal epithelia (32).…”

Oxidized CaMKII promotes asthma through the activation of mast cells

“…Very recent studies have suggested that HDM can directly induce ROS generation, causing oxidative DNA damage and asthma-associated pathophysiology (8,43). Environmental allergens can either directly induce ROS production or promote local inflammatory processes that lead to the secondary production of ROS (6)(7)(8). Here, we demonstrated that CRE can induce ROS production and that the production was suppressed in ROS-resistant MMVVδ mice, suggesting that ox-CaMKII may participate in a feed forward circuit to increase ROS production in mast cells.…”

“…Exposure of the airway epithelium to environmental pollutants or allergens is known to induce oxidative stress either directly or through the induction of local inflammatory processes that lead to the secondary production of ROS (6)(7)(8). Previous studies suggest that the multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is within one of the downstream signaling pathways activated by ROS (9).…”

MD2 Facilitates Pollen and Cat Dander-Induced Innate and Allergic Airway Inflammation

“…Recent studies have identified a role of innate responses mediated by Toll-like receptor 4 (TLR4) in pollen-induced allergic inflammation. [4][5][6] One study reported that short ragweed pollen induces allergic conjunctivitis by stimulating TLR4-dependent TSLP (Thymic stromal lymphopoietin) secretion in sensitized mice. 4 Another study reported that the adaptive allergic immune responses to birch pollen extract was reduced in Tlr4 KO mice, thus implying a role of TLR4 in induction of allergic immune responses.…”