Leukotriene B4 (LTB4) is a potent signaling molecule belonging to the eicosanoid family, a class of lipid mediators derived from fatty acids. LTB4 is not stored but is rapidly generated on demand by specific immune cells in response to injury or infection. Its primary function is to act as a cellular distress signal, directing the immune system’s first responders to the precise location where they are needed.
How the Body Creates Leukotriene B4
The biosynthesis of LTB4 begins with arachidonic acid, a fatty acid component liberated from cell membrane phospholipids by the enzyme cytosolic phospholipase A2. This released arachidonic acid then enters the lipoxygenase pathway, requiring the enzyme 5-Lipoxygenase (5-LOX) for the first step. A nuclear membrane protein known as 5-LOX-activating protein (FLAP) is an essential co-factor that helps move the arachidonic acid substrate to the 5-LOX enzyme.
The action of 5-LOX converts arachidonic acid into an unstable intermediate product known as Leukotriene A4 (LTA4). In the final step, LTA4 is rapidly converted into the biologically active LTB4 by the enzyme Leukotriene A4 hydrolase (LTA4H). This entire production pathway is largely restricted to professional phagocytes, such as neutrophils, macrophages, and mast cells, which are the immune cells active in the early stages of an immune challenge.
LTB4 as a Key Messenger in Acute Inflammation
LTB4’s function in acute defense is primarily centered on its role as a chemoattractant, a chemical signal that guides cells toward a concentration gradient. It is one of the most effective molecules known for attracting neutrophils, the most abundant type of white blood cell, to the site of tissue damage or microbial invasion. This rapid recruitment process is known as chemotaxis and is necessary for pathogen clearance.
The molecule achieves this signaling through specific receptors found on the surface of immune cells, primarily Leukotriene B4 Receptor 1 (BLT1) and, to a lesser extent, BLT2. BLT1 is the high-affinity receptor, and its activation is the main driver of the pro-inflammatory response. When LTB4 binds to BLT1, it triggers a cascade of intracellular events that cause the neutrophil to change its shape, adhere to the blood vessel lining, and migrate through the vessel wall into the affected tissue.
LTB4 also activates the incoming immune cells, enhancing their ability to fight infection. It promotes the release of antimicrobial compounds, increases the production of reactive oxygen species, and stimulates the cell’s phagocytic capacity to engulf and destroy invaders. LTB4 acts as a local amplifier, ensuring that the initial immune response is swift and robust enough to contain the threat.
Connecting LTB4 to Chronic Disease States
While LTB4 is beneficial in acute defense, its sustained or excessive production moves the immune response from protective to pathological, leading to chronic inflammation. This dysregulation causes the continuous and inappropriate recruitment of immune cells, which in turn results in tissue damage characteristic of several long-term health conditions. The persistent over-recruitment of neutrophils, driven by high LTB4 levels, is a common feature in these diseases.
In rheumatoid arthritis, LTB4 is found in elevated concentrations within the synovial fluid of affected joints, a finding linked to the aggressive, neutrophil-driven inflammation that erodes cartilage and bone. The molecule drives the adhesion and accumulation of leukocytes in the joint, contributing to the painful, perpetual cycle of inflammation. Similarly, in inflammatory bowel disease (IBD), the chronic inflammation of the digestive tract is associated with increased LTB4 levels, where its continuous activity contributes to the inflammatory lesions seen in conditions like ulcerative colitis.
LTB4 also plays a role in skin conditions, such as psoriasis, an autoimmune disease characterized by rapid skin cell proliferation and inflammation. The molecule promotes the infiltration of various immune cells, including neutrophils, into the skin lesions, sustaining the inflammatory cycle that causes the visible plaques. In the lungs, LTB4 contributes to chronic respiratory diseases like asthma by promoting bronchial inflammation and the infiltration of neutrophils and eosinophils into the airways. The ongoing presence of these cells narrows the airways and leads to the symptoms associated with the condition.
Strategies for Controlling LTB4 Activity
Given its central role in driving harmful chronic inflammation, LTB4 and its associated pathway have become a focus for pharmacological intervention. Therapeutic strategies generally aim to either prevent the synthesis of the molecule or block its ability to signal immune cells. One approach is to inhibit the production of LTB4 by targeting the upstream enzyme, 5-LOX.
Drugs known as 5-LOX inhibitors, such as Zileuton, directly prevent the enzyme from initiating the conversion of arachidonic acid, thereby reducing the overall amount of LTB4 produced. Another strategy involves the use of antagonists for the 5-LOX-activating protein (FLAP), which effectively starves the 5-LOX enzyme of its necessary substrate, also blocking LTB4 synthesis.
The second main strategy is to block the LTB4 signal itself by using LTB4 receptor antagonists. These compounds specifically bind to the BLT1 receptor, preventing LTB4 from activating it and thus inhibiting the migration and activation of inflammatory cells like neutrophils.