BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL‐33 production

Abstract

Background: Epithelial cells (ECs) play a crucial role in allergic sensitization to inhaled protease allergens by instructing type 2 innate lymphoid cells (ILC2) and dendritic cells (DCs) via release of pro-type 2 cytokines, particularly interleukin-33 (IL-33). Leukotriene B4 (LTB4) is a well-known leukocyte chemoattractant via engagement of its receptor 1 (BLT1). However, the role of LTB4-BLT1 axis in allergic sensitization via activation of ECs is still unknown. Methods:We evaluated the effect of LTB4-BLT1 axis on IL-33 expression and ILC2 activation in vivo and in vitro. Chimeric mice were established to evaluate the contribution of BLT1 expression in nonimmune cell to allergic sensitization.Results: Genetical or pharmacological interruption of LTB4-BLT1 axis during sensitization phase markedly reduced papain-induced IL-33 expression, decreased ILC2 activation and DC migration, thereby impairing the priming of allergic Th2 responses. Furthermore, papain inhalation induced a rapid release of LTB4 preceding IL-33, and intranasal administration of LTB4 to naïve WT mice significantly increased IL-33 expression and ILC2 activation in lung, which was absent in Il33 −/− or Ltb4r1 −/− mice. Furthermore, BLT1 was expressed in primary mouse ECs or normal human bronchial ECs (NHBE), and papain induced LTB4 release by NHBE, which in turn amplified IL-33 production dependent on Akt activation via BLT1. Consequently, bone marrow chimeric mice lacking BLT1 in radio-resistant structural cells failed to develop allergic lung inflammation to papain. Conclusion:Our study reveals a functional role of LTB4-BLT1 axis in nonimmune cells, most likely lung ECs, in controlling allergic sensitization as an upstream regulator of IL-33.

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…Ro et al proposed a “MyD88‐5‐/12‐LO‐BLT2‐NF‐κB” cascade contributing to the asthmatic development and exacerbation via IL‐33–induced IL‐13 production from mast cells 74 . A following study claimed that LTB4‐BLT1 axis in nonimmune cells, most likely lung epithelial cells, functioned as an upstream controller of IL‐33 production, leading to ILC2 activation and a subsequent allergic Th2 response 75 . Herein, leukotriene B4 (LTB4) is a leukocyte chemoattractant via interaction with its receptors, both BLT1 and BLT2, lying on the upstream of inflammatory cascade 76 .…”

The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders

“…In addition to its important role as a neutrophil chemoattractant, another important role of the LTB 4 –BLT1 pathway (despite observations made more than two decades ago) was shown only recently; the pathway plays an important role in recruiting and activating T cells [71] and dendritic cells, the major antigen-presenting cell in the lung [49]. Allergen-specific memory T cells and IgE-specific antibodies are required for these responses.…”

Promotion of Myofibroblast Differentiation and Tissue Fibrosis by the Leukotriene B4–Leukotriene B4 Receptor Axis in Systemic Sclerosis

“…We next attempted to investigate the signaling pathway that mediates the myofibroblast differentiation induced by the LTB 4 -BLT1 axis. Since our previous work implicated phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling in myofibroblast differentiation in SSc patients (25), and Akt acts as a downstream factor of BLT1 signaling in nonimmune cells (26), we examined whether this pathway was responsible for the BLT1-induced differentiation of myofibroblasts. We found that pretreatment of the cells with the mTOR inhibitor rapamycin or the PI3K/Akt inhibitor LY294002 reversed the LTB 4 Furthermore, we found that exogenous LTB 4 induced phosphorylation of Akt, mTOR, S6 kinase (S6K), and glycogen synthase kinase 3β (GSK3β), in a time-dependent manner, but had no effect on the total protein levels of Akt, mTOR, S6K, and GSK3β ( Figures 3E and F).…”