Leukotrienes: Bridging the Inflammatory Gap in Asthma and Inflammatory Bowel Diseases (IBD)

Abstract

Leukotrienes are potent inflammatory lipid mediators produced primarily by immune cells. Inflammation, being the center stone of two major disease conditions, namely, asthma and inflammatory bowel disease (IBD), has led researchers to study the role of leukotrienes (LTs) in both these disease settings extensively. Several studies indicate a crucial role for LTs in the development and progression of IBD, whereas LTs, especially cysteinyl leukotrienes (cys-LTs), have been identified as the major contributors to asthma initiation and progression for over three decades. Additionally, the lungs and the gut share several common characteristics, including their exposure to the external environment, similar microbiome composition, and inflammatory responses. These similarities suggest a bidirectional relationship, supported by the increased risk of IBD in asthma patients and vice versa. However, the specific role of LTs in this lung-gut connection remains unclear. This review will examine how several common factors, such as physiology, microbiome, environment, and inflammatory mediators, especially LTs, modulate this crosstalk. The review also highlights in detail how altered leukotriene biosynthesis and signaling contribute to the pathogenesis of both asthma and IBD. Furthermore, we will consider the therapeutic implications of targeting leukotriene pathways for patients with concurrent asthma and IBD in the hope of developing more efficient treatment outcomes for these interconnected conditions. Finally, this review will very briefly explore the involvement of neuronal connections in mediating the lung-gut crosstalk.

Keywords: asthma; chronic inflammation; inflammatory bowel disease; inter‐organ communication; leukotrienes; lung–gut axis.

FIGURE 1

Schematic representation of the common factors in asthma and IBD. Figure created with Biorender.com.

FIGURE 2

Schematic of inflammatory mediators potentially involved in the lung–gut axis and their detailed contributions to both asthma and IBD. Figure created with Biorender.com.

FIGURE 3

Leukotriene biosynthesis pathway. Various stimuli trigger the phosphorylation and activation of cytosolic phospholipase A₂ (PLA₂), which releases arachidonic acid (AA) from membrane phospholipids. The 5‐lipoxygenase enzyme (5‐LO) and its molecular partner, 5‐LOX activating protein (FLAP), convert AA to 5‐hydroperoxyeicosatetraenoic acid (5‐HpETE) and then to an unstable intermediate leukotriene A₄ (LTA₄). LTA₄ is further converted to LTB₄ by the LTA₄ hydrolase enzyme. LTB₄ acts via two receptors, BLT1 or BLT2, to exert its chemo‐attractive signals. LTA₄ can also be converted to leukotriene C₄ (LTC₄) by its conjugation to glutathione via the action of LTC₄ synthase. LTC₄ is then extracellularly transported and sequentially converted to leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄) by γ‐glutamyl transpeptidase and dipeptidase, respectively. LTC₄, LTD₄, and LTE₄ act via three receptors, CysLT₁R, CysLT₂R, or CysLT₃R (less common receptor for LTE₄) to induce airway hyperresponsiveness, remodeling, bronchoconstriction, and immune cell recruitment. Figure created with Biorender.com.

FIGURE 4

Overview of the role of leukotrienes (LTs) in asthma: Allergen exposure can trigger the production of LTs from different cell types in the airway. LTB₄ acts as a chemoattractant for neutrophils and other immune cells such as macrophages and MCs, which rush to the site of injury and get activated, generating LTs. LTs mainly mediate the activation of Th2‐type immune response, which leads to the production of different inflammatory cytokines such as IL‐4, IL‐5, and IL‐13. IL‐4 mediates B cell activation, which in turn produces IgE antibodies. During the challenge phase, IgE binding to MCs causes degranulation and release of histamine, which contributes to asthma manifestations. IL‐5 mediates eosinophilic recruitment, activation, and degranulation, which contributes to further chronic inflammation. IL‐13 is essential to activate goblet cells to release mucus, resulting in airway hyperresponsiveness observed during asthma. Figure created with Biorender.com.

FIGURE 5

Overview of the role of leukotrienes (LTs) in IBD: LTs produced as a result of damaged epithelial barrier due to various traumatic events can contribute to enhanced epithelial barrier dysfunction, recruitment and activation of various immune cell components such as macrophages, DCs, and neutrophils. While neutrophils can promote further acute inflammation, macrophages release several pro‐inflammatory mediators such as tumor necrosis factor (TNF), IL‐6, and IL‐27. Elevated levels of TNF and IL‐6 from DCs can activate and differentiate CD4⁺ T cells into Th17 and Th1 lineages, thereby producing even more TNF, interferon gamma (IFNγ), IL‐17, and IL‐22. This enhanced release of cytokines potentially leads to chronic inflammation observed in IBD. Figure created with Biorender.com.