Importance of the leukotriene B4-BLT1 and LTB4-BLT2 pathways in asthma

Abstract

For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous metabolites in the blood, sputum, and bronchoalveolar lavage fluid from asthmatics or experimental animals adds support to this notion. However, targeting of the leukotriene pathways has had, in general, limited success. The single exception in asthma therapy has been targeting of the cysteinyl leukotriene receptor 1, which clinically has proven effective but only in certain clinical situations. Interference with 5-lipoxygenase has had limited success, in part due to adverse drug effects. The importance of the LTB4-BLT1 pathway in asthma pathogenesis has extensive experimental support and findings, albeit limited, from clinical samples. The LTB4-BLT1 pathway was shown to be important as a neutrophil chemoattractant. Despite observations made more than two decades ago, the LTB4-BLT1 pathway has only recently been shown to exhibit important activities on subsets of T lymphocytes, both as a chemoattractant and on lymphocyte activation, as well as on dendritic cells, the major antigen presenting cell in the lung. The role of BLT2 in asthma remains unclear. Targeting of components of the LTB4-BLT1 pathway offers innovative therapeutic opportunities especially in patients with asthma that remain uncontrolled despite intensive corticosteroid treatment.

Keywords: Asthma; BLT1; CD4 T lymphocytes; CD8 T lymphocytes; LTB4.

Figure 1

LTB4-BLT1-CD8+ T cell-IL-13 pathway in asthma pathogenesis. Following allergen ligation of IgE on the high affinity IgE receptor (FcεRI), mast cells are activated resulting in the production and release of LTB4. Activated CD8+ T_EFF increase expression of the high affinity receptor BLT1, ligation of the receptor by LTB4 results in the migration of CD8+ T_EFF to the lung where in the presence of IL-4, the cells transdifferentiate through a cascade of molecular events resulting in IL-13 release [1].

Figure 2

Importance of the LTB4-BLT1 pathway in dendritic cell activation and migration to regional lymph nodes resulting in CD8+ T_EFF cell activation. 1) In the lung mast cells, macrophages or neutrophils are activated releasing LTB4. 2) Lung DCs expressing BLT1 and exposed to antigen (Ag), increase BLT1 expression as well as CCR7, resulting in their migration to the regional lymph nodes (PBLN). 3) Here, the antigen-presenting DCs encounter naive CD8+ T cells resulting in activation, priming, and increased BLT1 expression. 4) Activated CD8+ T_EFF migrate to the airways following ligation of BLT1 by LTB4. 5) In the atopic environment in the lungs of allergic patients, IL-4 results in the transdifferentiation of CD8+ T_EFF for IL-13 production, resulting in AHR, mucus production, and airway inflammation. Ag: antigen TCR; TCR: T cell receptor; MHC: major histocompatibility complex.