Unraveling cysteinyl leukotrienes and their receptors in inflammation through the brain-gut-lung axis

Abstract

Cysteinyl leukotrienes (CysLTs), as potent lipid inflammatory mediators, play a pivotal role in systemic multi-organ inflammation and inter-organ communication through interactions with their receptors (CysLTRs). However, However, the function of CysLT3R is unclear and lacks a network of cross-organ metabolite interactions, and the clinical use of leukotriene receptor antagonists (LTRAs) has certain limitations. This review systematically synthesizes existing evidence and proposes future directions by clarifying receptor subtype specificity, optimizing targeted therapies, exploring CysLTs' applications in neuroimmunology, and elucidating the dual roles of CysLTs in chronic inflammation. It is indicated that CysLTs activate eosinophils, mast cells, and airway tuft cells, driving type 2 immune responses and mucus secretion in the lungs, thereby exacerbating respiratory diseases such as asthma. In the nervous system, CysLTs aggravate neurodegenerative disorders like cerebral ischemia and Alzheimer's disease by disrupting the blood-brain barrier, promoting glial activation, and inducing neuronal damage. In the gut, CysLTs regulate anti-helminth immunity via the tuft cell-ILC2 pathway and collaborate with prostaglandin D2 (PGD2) to modulate bile excretion and mucosal protection. Furthermore, CysLTs mediate communication through the gut-lung and gut-brain axes via metabolites such as succinate, contributing to cross-organ inflammatory regulation. In conclusion, this review highlights the complex roles of CysLTs in chronic inflammation, providing a theoretical foundation for precise intervention in multi-organ inflammatory diseases, which provides a theoretical framework for precision interventions in multi-organ inflammatory diseases and inspires interdisciplinary breakthroughs.

Keywords: Cysteinyl; gut-brain axis; gut-lung axis; inflammation; leukotriene.

Figure 1.

Synthesis, action receptors, and receptor inhibitors of leukotrienes (LTs). Arachidonic acid serves as the primary precursor for LTs synthesis. It is oxidized by 5-lipoxygenase (5-LO) to generate the intermediate LTA4, after which LT production diverges into two metabolic pathways: one branch involves LTA4 conversion by LTC4 synthase (LTC4S) into LTC4 (a cysteinyl leukotriene, CysLTs), which is subsequently metabolized to LTD4 and LTE4. The other branch utilizes LTA4 hydrolase (LTA4H) to produce LTB4 (a dihydroxy acid leukotriene). Synthesis and release: LTB4 and LTC4 are primarily synthesized intracellularly and exported via transport proteins to act on receptors or generate other LTs. Receptors and inhibitors: 1. BLT: BLT1 Binds LTB4 with high affinity, mediating inflammatory responses. Antagonists include LY293111 and BIIL284. BLT2: primarily associated with tissue repair. 2. CysLTR: CysLT1R: preferentially binds LTD4. Antagonists include Montelukast and Zafirlukast. CysLT2R: Binds both LTC4 and LTD4. Antagonists include HAMI3379 and BayCysLT2. CysLT3R (GPR99): selectively responds to LTE4 but can also be activated by LTC4/LTD4. (figure was created by Figdraw).

Figure 2.

The role of CysLTs in lung injury. By activating different receptors, cysLTs play diverse roles in the lungs. 1. The activation of CysLT1R can trigger degranulation of eosinophils, releasing granule contents including eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil peroxidase (EPX), and eosinophil-derived neurotoxin, among others. These released granule contents can damage tissue cells, activate immune cells such as neutrophils and mast cells, and enhance the Th2 immune response. Eosinophils can also release various cytokines, such as IL-4, IL-5, and IL-13, which can affect the differentiation and proliferation of CD4+ T cells. Furthermore, ILC2s activated by CysLTs can rapidly secrete multiple type 2 cytokines, which are key mediators of type 2 immune responses and can further recruit and activate more immune cells, such as Th2 cells, thereby amplifying the inflammatory response. Alveolar macrophages, upon activation by CysLT1R, release inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8), exacerbating lung inflammation, while the upregulation of the P2Y6 signaling pathway can alleviate inflammation by inhibiting CysLT1R. 2. The activation of CysLT2R primarily manifests in the induction of HMGB1 expression on the surface of platelets, a change that can promote their firm adhesion to eosinophils, facilitate degranulation, and participate in the initiation of inflammation. 3. Research on CysLT3R is still in its infancy, and its activation mainly synergizes with IL-25-dependent signaling pathways to induce the expansion of tuft cells in the airways, leading to the occurrence of type 2 lung inflammation. (figure was created by Figdraw).

Figure 3.

The role of CysLTs and their receptors in brain-gut-lung axis communication. Gut microbiota metabolites (e.g. short-chain fatty acids, bile acids) regulate systemic immunity via the gut-lung axis, with an anatomical basis rooted in the endodermal homology of the lungs and intestines. CysLTs exhibit dual roles in the gut-lung axis: in the gut, they enhance anti-helminth immunity by activating the tuft cell-ILC2 pathway, while in the respiratory tract, they mediate leukotriene-dependent type 2 allergic inflammation. Succinate, a key metabolite, synergizes with CysLTs in the gut to initiate immune defense but exacerbates gut-originated lung injury via the SUCNR1 pathway, suggesting CysLTs’ potential hub role in cross-organ inflammation. Bidirectional gut-brain communication involves immune cell migration, neural transmission, and microbiota metabolite regulation, where psychological stress and gut inflammation mutually disrupt neuroimmune homeostasis. Studies indicate that CysLTs may participate in gut-brain interactions by modulating brain decision-making circuits (e.g. inducing allergen-avoidance behaviors), and their receptor expression in neural nociceptive pathways implies conservation of related mechanisms in humans. (figure was created with by Figdraw).