Hubbry Logo
Leukotriene B4Leukotriene B4Main
Open search
Leukotriene B4
Community hub
Leukotriene B4
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Leukotriene B4
Leukotriene B4
Leukotriene B4
View on Wikipedia
from Wikipedia
Leukotriene B4
Names
Preferred IUPAC name
(5S,6Z,8E,10E,12R,14Z)-5,12-Dihydroxyicosa-6,8,10,14-tetraenoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C20H32O4/c1-2-3-4-5-6-9-13-18(21)14-10-7-8-11-15-19(22)16-12-17-20(23)24/h6-11,14-15,18-19,21-22H,2-5,12-13,16-17H2,1H3,(H,23,24)/b8-7+,9-6-,14-10+,15-11-/t18-,19-/m1/s1 ☒N
    Key: VNYSSYRCGWBHLG-AMOLWHMGSA-N ☒N
  • InChI=1/C20H32O4/c1-2-3-4-5-6-9-13-18(21)14-10-7-8-11-15-19(22)16-12-17-20(23)24/h6-11,14-15,18-19,21-22H,2-5,12-13,16-17H2,1H3,(H,23,24)/b8-7+,9-6-,14-10+,15-11-/t18-,19-/m1/s1
    Key: VNYSSYRCGWBHLG-AMOLWHMGBE
  • CCCCC/C=C\C[C@H](/C=C/C=C/C=C\[C@H](CCCC(=O)O)O)O
Properties
C20H32O4
Molar mass 336.472 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice.

Biochemistry

[edit]

LTB4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammatory mediators and is able to induce the adhesion and activation of leukocytes on the endothelium, allowing them to bind to and cross it into the tissue.[1] In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.[1] It is synthesized by leukotriene-A4 hydrolase from leukotriene A4.[2]

Eicosanoid synthesis (leukotrienes at right)

Diabetes

[edit]

A study at the University of California, San Diego School of Medicine has shown that LTB4 promotes insulin resistance in obese mice.[3] Obesity is the major cause of insulin resistance in type 2 diabetes.[4]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Leukotriene B4

View on Grokipedia
from Grokipedia
Leukotriene B4 (LTB4) is a potent pro-inflammatory mediator derived from the metabolism of through the 5-lipoxygenase pathway, serving primarily as a chemoattractant for neutrophils, monocytes, and during acute and chronic inflammatory responses. It is biosynthesized in leukocytes such as neutrophils and macrophages via sequential enzymatic actions: is first converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by 5-lipoxygenase (5-LOX) in conjunction with the 5-lipoxygenase-activating protein (FLAP), then to the unstable leukotriene A4 (LTA4), and finally hydrolyzed to LTB4 by LTA4 (LTA4H). Chemically, LTB4 is (6Z,8E,10E,14Z)-5S,12R-dihydroxyeicosa-6,8,10,14-tetraenoic acid, featuring two hydroxyl groups at positions 5 and 12 that contribute to its . LTB4 exerts its effects by binding to two G protein-coupled receptors: BLT1, a high-affinity receptor predominantly expressed on leukocytes that couples to Gi/o proteins to mediate , , and of immune cells; and BLT2, a low-affinity receptor with broader tissue distribution that couples to Gq, G11, and G14 proteins and recognizes additional ligands like 12-HETE. Upon receptor , LTB4 promotes key leukocyte functions, including migration to sites, enhanced to via upregulation of , , anion generation, and production, thereby amplifying innate immune responses. It also contributes to host defense against infections but can drive pathological when dysregulated. In disease contexts, elevated LTB4 levels are implicated in conditions such as , , (COPD), cardiovascular disorders, and certain cancers, where it sustains infiltration and tissue damage. Therapeutic strategies targeting the LTB4 pathway, including inhibitors of 5-LOX or LTA4H and BLT1 antagonists, are under investigation to mitigate these inflammatory processes. Structural studies of BLT1 have revealed critical ligand-binding residues, aiding drug design efforts.

Discovery and Chemical Properties

Discovery and Historical Context

Leukotriene B4 (LTB4) was first identified in 1979 by Pierre Borgeat and Bengt Samuelsson during investigations into the metabolism of in polymorphonuclear leukocytes. Their work revealed LTB4 as a novel dihydroxy derivative formed when rabbit polymorphonuclear leukocytes, isolated from peritoneal exudates, were stimulated with the calcium A23187 in the presence of . This metabolite was detected through and characterized as a potent polar distinct from previously known hydroxy acids like 5-HETE. Shortly thereafter, the same group extended these findings to human polymorphonuclear leukocytes, confirming LTB4 production under similar conditions and highlighting an unstable epoxide intermediate in its formation. The structural elucidation of LTB4 was completed by Samuelsson's team in 1980 using advanced techniques such as , , and isotopic labeling to trace the incorporation of molecular oxygen. This confirmed LTB4 as 5(S),12(R)-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid, derived from the precursor via the 5-lipoxygenase pathway. These late-1970s isolations from leukocytes marked a pivotal advancement in understanding inflammatory mediators beyond prostaglandins. Initial biological characterization in 1980 by A.W. Ford-Hutchinson and colleagues demonstrated LTB4's potency as a chemoattractant, eliciting directed migration and aggregation of at nanomolar concentrations in assays using rabbit peritoneal exudates and human peripheral blood . Early experimental methods relied on bioassays, including contractions of isolated strips to assess smooth muscle-stimulating activity and under-agarose or Boyden chamber tests to quantify . These findings underscored LTB4's role in leukocyte recruitment during . The broader research, including LTB4, contributed to Bengt Samuelsson sharing the 1982 in Physiology or with Sune and John for discoveries on prostaglandins and related substances.

Chemical Structure and Physical Properties

Leukotriene B4 (LTB4) is a dihydroxy derivative of , characterized by a 20-carbon polyunsaturated chain with the molecular formula C20H32O4 and a molecular weight of 336.47 g/mol. Its structure features a group at carbon 1, hydroxyl groups at carbons 5 and 12, and four double bonds positioned at 6-7 ( configuration), 8-9 (), 10-11 (), and 14-15 (), forming a conjugated triene system between positions 6 and 10 that contributes to its biological reactivity. The biologically active form of LTB4 exhibits specific , with the all-trans configuration in the triene moiety and chiral centers at C5 (S) and C12 (R), designated as (5S,12R)-6Z,8E,10E,14Z-eicosatetraenoic acid. This stereoisomeric configuration is essential for its potent pro-inflammatory activity, distinguishing it from less active isomers such as 5S,12S-LTB4 or 6-trans-LTB4. LTB4 is a lipophilic , appearing as a clear, colorless solution, and exhibits low in but high in organic solvents such as and (DMSO). The conjugated triene system imparts characteristic UV absorption with a maximum at approximately 270 nm and shoulders at 261 nm and 281 nm, enabling its detection in analytical assays.46220-X/pdf) In comparison to cysteinyl leukotrienes such as LTC4, LTD4, and LTE4, LTB4 lacks the polar or conjugate at C6, resulting in greater and distinct membrane permeability properties that influence their respective roles in .

Biosynthesis and Metabolism

Biosynthetic Pathway

Leukotriene B4 (LTB4) is synthesized through the 5-lipoxygenase (5-LOX) branch of the eicosanoid pathway, which diverges from the (COX) pathway responsible for production. , a polyunsaturated stored in phospholipids, serves as the common precursor for both pathways. Upon cellular activation, is mobilized and directed toward primarily in immune cells, where it undergoes oxidative metabolism to generate potent inflammatory mediators like LTB4. The biosynthetic pathway begins with the release of from membrane phospholipids by cytosolic A2α (cPLA2α), which is activated by increased intracellular calcium levels. Subsequently, 5-LOX, in conjunction with its activating protein FLAP, catalyzes the oxygenation of at the C-5 position to form 5(S)-hydroperoxyeicosatetraenoic acid (5-HPETE). This intermediate is rapidly dehydrated by 5-LOX to yield the unstable leukotriene A4 (LTA4). Finally, LTA4 is hydrolyzed by LTA4 (LTA4H) to produce LTB4, completing the core synthetic sequence. This multistep process, first elucidated in polymorphonuclear leukocytes, ensures efficient production of LTB4 in response to physiological demands. Biosynthesis of LTB4 occurs predominantly in leukocytes, including neutrophils and macrophages, where the key enzymes localize to the nuclear and perinuclear membranes. The 5-LOX enzyme translocates from the to these membranes upon stimulation, facilitated by FLAP, an that presents to 5-LOX and stabilizes the complex for optimal . This enhances the efficiency of leukotriene formation in inflammatory microenvironments. The pathway is tightly regulated by inflammatory stimuli such as cytokines, , calcium ionophores, and cellular stressors like ATP, which trigger calcium influx and events. For instance, of 5-LOX at specific serine residues by kinases like MAPK can modulate its activity, while promotes translocation and synthesis. These regulatory mechanisms ensure that LTB4 production is inducible and context-specific, aligning with host defense needs.

Key Enzymes and Regulation

The biosynthesis of leukotriene B4 (LTB4) relies on three principal enzymes: 5-lipoxygenase (5-LOX or ALOX5), 5-LOX-activating protein (FLAP), and leukotriene A4 hydrolase (LTA4H). These proteins form a coordinated complex at the nuclear membrane, where 5-LOX initiates the oxygenation of , FLAP facilitates substrate presentation, and LTA4H completes the conversion to the bioactive dihydroxy acid LTB4. 5- is an iron-containing dioxygenase that catalyzes the initial steps in LTB4 production, converting to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and subsequently to the unstable leukotriene A4 (LTA4). Its , resolved at 2.4 Å resolution, reveals a conserved lipoxygenase fold comprising a β-sheet-rich N-terminal domain and an α-helical catalytic domain, with the iron cofactor coordinated by and residues at the . This architecture positions the enzyme for stereospecific oxygen insertion at the 5-position of , a rate-limiting step tightly controlled by cellular stimuli such as calcium influx and . FLAP serves as a membrane-bound chaperone essential for 5-LOX function, anchoring the enzyme to the nuclear envelope and enabling access to arachidonic acid substrates sequestered in phospholipid bilayers. By forming a scaffold-like complex with 5-LOX, FLAP promotes the transfer of arachidonic acid to the enzyme's active site, which is otherwise occluded by a structural "cork" involving aromatic residues like Phe-177 and Tyr-181; mutations alleviating this barrier enhance catalysis in vitro. Although direct inhibitors of FLAP (e.g., MK-886) block leukotriene synthesis by disrupting this interaction, drugs like zileuton primarily target 5-LOX itself, indirectly highlighting FLAP's indispensability in vivo. Leukotriene A4 hydrolase is a bifunctional metalloprotease that hydrolyzes the LTA4 to yield LTB4, the committed step in its formation. Its demonstrates a deep active-site cleft housing the Zn²⁺ , coordinated by two histidines, a glutamate, and a , facilitating nucleophilic attack on the LTA4 ring to produce the conjugated triene . LTA4H also possesses activity, cleaving N-terminal residues from peptides like proline-glycine-proline, which generates pro-inflammatory signals independent of LTB4; this dual functionality allows selective modulation, as some inhibitors block hydrolysis while sparing peptidase action to promote resolution of . Regulation of these enzymes occurs at multiple levels to fine-tune LTB4 production in response to inflammatory cues. Transcriptionally, the ALOX5 gene is upregulated by signaling, with 5-LOX physically interacting with subunits (e.g., and c-Rel) to enhance expression of target genes like kynureninase while repressing others such as COX-2. Post-translationally, modulates 5-LOX localization and activity; for instance, PKA-mediated at Ser523 inhibits and sequesters the enzyme in the , whereas MAPKAPK-2/3 or ERK at Ser271 promotes nuclear retention and leukotriene synthesis. Genetic polymorphisms in the ALOX5 promoter, particularly Sp1 variants (e.g., rs59439148), reduce basal expression and correlate with lower urinary E4 levels, while homozygous minor alleles are associated with elevated cysteinyl production, diminished lung function, and poorer control in children. Pharmacological inhibition of 5-LOX represents a key therapeutic strategy to curb LTB4-mediated . Zileuton, the only clinically approved 5-LOX inhibitor, reversibly binds the to block , including LTB4, thereby attenuating , mucus secretion, and recruitment in . Administered orally at 600 mg four times daily or as extended-release tablets twice daily, it is indicated for prophylaxis in chronic patients aged 12 and older, often as an add-on to inhaled corticosteroids, though its short half-life limits broader use.

Metabolism and Inactivation

Leukotriene B4 (LTB4) is primarily inactivated through oxidative metabolism, ensuring its rapid clearance to limit pro-inflammatory effects. The dominant pathway involves ω-oxidation mediated by enzymes of the CYP4F subfamily, which hydroxylate LTB4 at the terminal carbon (C-20) to form 20-hydroxy-LTB4 (20-OH-LTB4). This initial step is catalyzed by CYP4F3 in granulocytes and CYP4F2 in hepatocytes, with further oxidation yielding 20-carboxy-LTB4 (20-COOH-LTB4) and ultimately 20-dicarboxy-LTB4, rendering the molecule biologically inactive. In mouse models, CYP4F18 specifically drives this ω-oxidation in neutrophils, and its deficiency abolishes detectable ω-hydroxylated LTB4 products without compensation by other CYP4F isoforms. Following ω-oxidation, the metabolites undergo chain shortening via β-oxidation in peroxisomes, producing shorter-chain compounds akin to 12-hydroxyeicosatetraenoic acid (12-HETE) derivatives that are further degraded to in mitochondria. This peroxisomal process, involving enzymes such as and , represents a major catabolic route for hydroxylated eicosanoids like LTB4, facilitating their excretion. Minor inactivation routes include glutathione conjugation, which forms polar conjugates for enhanced solubility and elimination, though this is less prominent than oxidative pathways. Metabolites are exported from cells via ATP-binding cassette transporters, notably multidrug resistance protein 4 (MRP4/ABCC4), which effluxes LTB4 conjugates across membranes to support systemic clearance. The plasma half-life of LTB4 is extremely short, approximately 0.5 minutes in experimental models, reflecting rapid enzymatic degradation and contributing to its transient signaling. In tissues, clearance may be somewhat prolonged due to localized expression, but overall, this brevity confines LTB4's action to seconds to minutes. Inflammation upregulates CYP4F enzymes, accelerating inactivation to resolve responses, while genetic polymorphisms in CYP4F2 and CYP4F3 can impair ω-oxidation efficiency, potentially altering LTB4 levels in states.

Receptors and Molecular Signaling

Receptor Subtypes

Leukotriene B4 (LTB4) primarily signals through two distinct G protein-coupled receptors (GPCRs), BLT1 and BLT2, which differ in affinity, expression, and ligand specificity. BLT1, encoded by the LTB4R gene, functions as the high-affinity receptor for LTB4, with a (Kd) of approximately 1 nM. It is predominantly expressed on leukocytes, including neutrophils and . BLT1 couples to Gαi/o proteins, facilitating pertussis toxin-sensitive signaling. Cryo-electron (cryo-EM) structures of LTB4-bound BLT1 in complex with protein, resolved at 2.91 Å in 2022, reveal a binding pocket formed by transmembrane helices with a hydrophobic and polar residues. Key interactions include Arg2677.35 forming a network via molecules to the C5 hydroxyl group of LTB4, and Asn2687.36 directly contacting the C1 carboxyl group. BLT2, encoded by the LTB4R2 gene, serves as the low-affinity receptor for LTB4, exhibiting a Kd of approximately 23 nM. It displays broader tissue expression, including on mast cells and epithelial cells, and couples primarily to Gαq proteins. Unlike BLT1, BLT2 also binds other eicosanoids, such as 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). Expression of both BLT1 and BLT2 is upregulated during inflammatory conditions through NF-κB-dependent mechanisms, as demonstrated in vascular cells and macrophages exposed to cytokines like IL-1β. Gene-targeted knockout mice studies confirm non-redundant functions for each receptor in immune responses. Species variations exist between and orthologs; for instance, BLT2 exhibits greater amino acid sequence identity (78.6%) across humans and mice compared to BLT1, potentially influencing binding and expression patterns.

Downstream Signaling Mechanisms

Leukotriene B4 (LTB4) exerts its effects primarily through two G protein-coupled receptors, BLT1 and BLT2, which activate distinct yet overlapping intracellular signaling cascades. BLT1, the high-affinity receptor, couples predominantly to Gαi proteins, inhibiting adenylyl cyclase and thereby reducing cyclic AMP (cAMP) levels to modulate cellular responses in leukocytes. This Gαi-mediated pathway is pertussis toxin-sensitive and essential for downstream events in inflammatory cells. Concurrently, BLT1 engages the phospholipase Cβ (PLCβ) pathway, hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of Ca²⁺ from endoplasmic reticulum stores, elevating cytosolic Ca²⁺ concentrations, while DAG activates PKC isoforms. Calcium imaging studies in human monocytes have confirmed Ca²⁺ mobilization upon LTB4 binding to BLT1. Furthermore, BLT1 stimulates phosphorylation of the MAPK/ERK cascade, as evidenced by Western blot assays in HEK293 cells transiently transfected with BLT1, where LTB4 induces dose-dependent ERK activation within minutes. BLT2, the low-affinity receptor with broader tissue expression, couples mainly to Gαq proteins, directly activating PLC to generate IP3 and DAG, thereby increasing intracellular Ca²⁺ and stimulating PKC activity. This Gαq-PLC axis results in Ca²⁺ responses. BLT2 signaling also activates the (PI3K)-Akt pathway, which enhances cell survival by phosphorylating Akt at Ser473, as observed in lysates following LTB4 exposure. Both BLT1 and BLT2 share activation of the (PI3K)-Akt pathway, which enhances cell survival by phosphorylating Akt at Ser473, as observed in lysates following LTB4 exposure. β-Arrestin recruitment to phosphorylated receptors occurs for both subtypes, mediating desensitization by uncoupling G proteins and promoting clathrin-dependent internalization, confirmed by in BLT1- and BLT2-expressing cells.

Physiological Roles

Chemotaxis and Leukocyte Activation

Leukotriene B4 (LTB4) serves as a potent chemoattractant for neutrophils and , primarily through high-affinity binding to the BLT1 receptor, which enables gradient sensing and directed migration at picomolar to nanomolar concentrations. In neutrophils, LTB4 facilitates by amplifying polarization and , often acting as a secondary signal relay to extend the range of primary chemoattractants like formyl-methionyl-leucyl-phenylalanine (fMLP). This process is particularly effective in transendothelial migration, where LTB4 promotes neutrophil adherence and traversal of the vascular barrier to reach inflammatory sites. studies using Boyden chamber assays demonstrate that LTB4 induces maximal neutrophil migration with an of approximately 1 nM, highlighting its sensitivity and potency in controlled gradient environments. Beyond , LTB4 activates key functional responses in leukocytes, particularly and monocytes, while exerting weaker effects on T cells and B cells due to lower receptor expression and affinity. In , LTB4 triggers by promoting BLT1 and activation of the Yes , leading to the release of lysosomal enzymes essential for clearance. It also stimulates NADPH oxidase assembly, resulting in robust (ROS) production via Rac-ERK signaling pathways, which enhances microbial killing but can contribute to tissue damage if dysregulated. Additionally, LTB4 activates , notably LFA-1 (CD11a/CD18), by inducing conformational changes that increase adhesion to , as evidenced by enhanced homotypic aggregation and antibody binding to activation epitopes at 10 nM concentrations. LTB4 further modulates leukocyte activation by promoting cytokine release, with potent effects on neutrophils and monocytes. In neutrophils, it directly induces interleukin-8 (IL-8) secretion and potentiates tumor necrosis factor-α (TNF-α) production in response to Toll-like receptor ligands, amplifying inflammatory signaling. Monocytes exhibit strong chemotactic responses to LTB4 via BLT1, with activation leading to increased production of IL-6, IL-1, and monocyte chemoattractant protein-1 (), which reinforce recruitment loops. In contrast, T and lymphocytes show minimal migration to LTB4, reflecting its specialized role in innate immune cells over adaptive ones. Although primarily targeting leukocytes, LTB4 indirectly influences non-immune cells by activating endothelial permeability through neutrophil-dependent mechanisms, such as granule protein release that disrupts barrier .

Role in Host Defense and

Leukotriene B4 (LTB4) plays a pivotal role in host defense by recruiting , such as neutrophils and macrophages, to sites of , thereby facilitating the containment and elimination of pathogens. In bacterial formation, macrophage-derived LTB4 promotes the organized accumulation of immune cells, enhancing abscess architecture and bacterial clearance during skin infections like those caused by . Furthermore, LTB4 augments microbial killing mechanisms, including the production of (ROS) in neutrophils and the formation of (NETs) through signaling pathways involving its receptors, which trap and kill effectively. In acute inflammation, occurring within the initial 0-24 hours, LTB4 amplifies the response through synergy with complement component C5a, where C5a-induced LTB4 release from immune cells enhances recruitment and activation at inflammatory sites. This coordination promotes , particularly when LTB4 acts in concert with vasodilators like , allowing plasma proteins and leukocytes to extravasate and initiate the inflammatory cascade. LTB4 contributes indirectly to the resolution of inflammation by supporting recruitment, which facilitates of apoptotic cells and pro-resolving functions in . This process is counterbalanced by omega-3-derived , such as protectin D1, which restore the balance between pro-inflammatory LTB4 and signals to facilitate timely resolution. Animal models underscore LTB4's protective functions; for instance, mice deficient in 5-lipoxygenase (the enzyme upstream of LTB4 synthesis) exhibit impaired bacterial clearance in the lungs, associated with reduced phagocytic activity of alveolar macrophages during infections. Similarly, LTB4 receptor BLT1 knockout mice show diminished recruitment and increased susceptibility to pulmonary pathogens, highlighting LTB4's essential role in innate immunity. Evolutionarily, the LTB4 biosynthetic and signaling pathways are highly conserved across mammals, underscoring their fundamental contribution to innate immune responses against infections. Recent studies (as of 2025) have further elucidated LTB4's roles, including platelet-derived LTB4 in amplifying recruitment and LTB4-mediated regulation of T cell recognition in controlling infections.

Pathological Implications

Involvement in Inflammatory Diseases

Leukotriene B4 (LTB4) plays a significant role in the of various chronic inflammatory diseases by promoting leukocyte recruitment and sustaining inflammatory cascades through its receptors, particularly BLT1. In these conditions, elevated LTB4 levels amplify immune cell infiltration and tissue damage, contributing to disease progression beyond its physiological functions in host defense. In and allergic diseases, LTB4 drives recruitment to the airways, exacerbating airway and hyperresponsiveness. Levels of LTB4 are elevated in fluid from patients with nocturnal and severe persistent , correlating with eosinophilic infiltration and disease severity. The LTB4/BLT1 pathway is implicated in severe variants, including aspirin- and exercise-induced forms, where it enhances and activation. Antagonists targeting BLT1, such as those explored in early clinical trials, have shown potential but faced challenges; for instance, compounds like those in the LTB4 pathway were tested in Phase II studies for but did not advance due to limited efficacy. In (RA), synovial LTB4 levels are markedly increased and correlate with joint destruction and disease activity. LTB4 promotes activation by engaging BLT1 and BLT2 receptors on precursors, leading to intracellular calcium mobilization and enhanced osteoclastogenesis, which contributes to bone erosion in affected joints. This mechanism underscores LTB4's role in the destructive synovial inflammation characteristic of RA. Psoriasis involves keratinocyte-derived LTB4, which sustains plaque formation through autocrine and via BLT2. LTB4 stimulates keratinocyte proliferation and migration, amplifying epidermal in psoriatic lesions, while also recruiting neutrophils to perpetuate . Topical inhibitors targeting LTB4 pathways have been investigated as potential therapies to disrupt this cycle and improve in psoriatic . In (IBD), particularly , LTB4 concentrations are elevated in the colonic mucosa, driving mucosal and epithelial damage. The LTB4/BLT1 axis is critical in dextran sulfate sodium (DSS)-induced models, where BLT1 signaling promotes Th1/Th17 differentiation and neutrophil influx, worsening tissue injury. Blocking this pathway in preclinical models ameliorates severity, highlighting its therapeutic potential. Recent studies post-2020 have linked LTB4 to hyper in severe , where elevated systemic LTB4 levels correlate with disease severity, especially in patients with comorbidities like , by enhancing storms and immune cell dysregulation. In , persistent LTB4 elevation has been observed, potentially contributing to ongoing via BLT1-mediated pathways, as suggested in 2023 analyses of mediators in post-acute sequelae.

Associations with Metabolic and Other Disorders

Leukotriene B4 (LTB4) contributes to metabolic dysregulation in by promoting through enhanced infiltration into , where it exacerbates chronic low-grade and impairs insulin signaling via the LTB4/BLT1 axis. Elevated LTB4 levels have been observed in the serum of patients with , correlating with disease severity and complications. In , LTB4 drives BLT1-mediated glomerular , leading to injury and progression, as demonstrated in preclinical models where BLT1 blockade ameliorates renal damage. In atherosclerosis, LTB4 facilitates the chemotaxis of monocytes to vascular plaques, promoting their recruitment and differentiation into foam cells via BLT1 signaling, which accelerates formation and . A seminal 2002 study from the highlighted how LTB4/BLT1 interactions drive foam cell accumulation in hypercholesterolemic models, with antagonism reducing plaque progression by up to 60%. Defects in LTB4 omega-oxidation further exacerbate by prolonging its inflammatory effects and enhancing development in susceptible models. LTB4 exhibits dual roles in cancer, acting as pro-tumorigenic in and colon malignancies by stimulating and through BLT1 and BLT2 receptors, which support expression and metastatic spread. Conversely, in certain contexts, LTB4 enhances anti-tumor immunity by activating natural killer cells and + T cells via BLT1, promoting tumor infiltration and , as evidenced in syngeneic tumor models. A in Signal Transduction and Targeted Therapy underscores these context-dependent BLT1/BLT2 functions, noting LTB4's potential to either suppress or accelerate tumor progression based on immune cell involvement. Beyond metabolic and neoplastic disorders, LTB4 worsens by amplifying systemic inflammation and vascular leakage, contributing to through excessive activation and release. In , LTB4 mediates crystal-induced recruitment and activation in , perpetuating acute flares via BLT1-dependent . For , LTB4 stimulates adventitial fibroblast proliferation, migration, and collagen deposition in a dose-dependent manner, driving remodeling in models. Therapeutically, BLT1 antagonists like CP-105696 have shown promise in preclinical metabolic models, reducing in diet-induced by limiting adipose accumulation and improving glucose . Similar antagonism attenuates progression in apolipoprotein E-deficient mice by inhibiting formation. Dietary interventions that reduce precursors, such as omega-3 fatty acid supplementation, lower LTB4 production and mitigate associated metabolic inflammation in and models.

References

  1. https://pubmed.ncbi.nlm.nih.gov/29042025/
  2. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/leukotriene-b4
  3. https://www.nature.com/articles/s41467-021-23149-1
  4. https://www.pnas.org/doi/10.1073/pnas.76.5.2148
  5. https://www.pnas.org/doi/10.1073/pnas.76.7.3213
  6. https://www.nobelprize.org/prizes/medicine/1982/samuelsson/lecture/
  7. https://www.nature.com/articles/286264a0
  8. https://www.nobelprize.org/prizes/medicine/1982/press-release/
  9. https://www.lipidmaps.org/databases/lmsd/LMFA03020001
  10. https://pubs.acs.org/doi/10.1021/ja00547a051
  11. https://pubmed.ncbi.nlm.nih.gov/6086758/
  12. https://www.sciencedirect.com/topics/veterinary-science-and-veterinary-medicine/leukotriene-b4
  13. https://onlinelibrary.wiley.com/doi/pdf/10.1100/tsw.2007.187
  14. https://doi.org/10.1172/JCI97945
  15. https://doi.org/10.1016/j.smim.2017.07.012
  16. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.161.supplement_1.ltta-1
  17. https://doi.org/10.1172/JCI117889
  18. https://pubmed.ncbi.nlm.nih.gov/21233389/
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC4777300/
  20. https://pubmed.ncbi.nlm.nih.gov/11175901/
  21. https://www.nature.com/articles/s41388-024-03016-1
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC3633142/
  23. https://www.ncbi.nlm.nih.gov/books/NBK448202/
  24. https://www.nature.com/articles/s41392-020-00443-w
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC2687325/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC4013684/
  27. https://www.sciencedirect.com/topics/medicine-and-dentistry/icosanoid-metabolism
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC1910361/
  29. https://pubmed.ncbi.nlm.nih.gov/12895595/
  30. https://rupress.org/jem/article/192/3/421/25895/A-Second-Leukotriene-B4-Receptor-Blt2A-New
  31. https://www.nature.com/articles/s41467-022-28820-9
  32. https://www.pnas.org/doi/10.1073/pnas.0505845102
  33. https://www.jci.org/articles/view/43302
  34. https://pubmed.ncbi.nlm.nih.gov/36908237/
  35. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2012.00119/full
  36. https://www.ahajournals.org/doi/10.1161/01.atv.0000092941.77774.3c
  37. https://pubmed.ncbi.nlm.nih.gov/26813973/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC6741447/
  39. https://rupress.org/jem/article/192/3/439/25903/Bltr-Mediates-Leukotriene-B4-Induced-Chemotaxis
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC4141281/
  41. https://ashpublications.org/blood/article/135/12/891/431048/NADPH-oxidase-controls-pulmonary-neutrophil
  42. https://pubmed.ncbi.nlm.nih.gov/7687238/
  43. https://pubmed.ncbi.nlm.nih.gov/15271789/
  44. https://link.springer.com/article/10.1007/BF00916243
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC6107286/
  46. https://pubmed.ncbi.nlm.nih.gov/39303536/
  47. https://pubmed.ncbi.nlm.nih.gov/38440842/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC7905230/
  49. https://pubmed.ncbi.nlm.nih.gov/6295113/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC2176035/
  51. https://www.nature.com/articles/s41598-017-13154-0
  52. https://www.nature.com/articles/ncomms12859
  53. https://www.nature.com/articles/s41598-017-17993-9
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC5768911/
  55. https://www.sciencedirect.com/science/article/pii/S2473952925001466
  56. https://pubmed.ncbi.nlm.nih.gov/40835209/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC5679233/
  58. https://pubmed.ncbi.nlm.nih.gov/2546985/
  59. https://www.atsjournals.org/doi/10.1165/rcmb.2018-0175OC
  60. https://www.sciencedirect.com/science/article/pii/S1044532316301336
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC4276054/
  62. https://www.clinexprheumatol.org/article.asp?a=13657
  63. https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-014-0496-y
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC9459139/
  65. https://onlinelibrary.wiley.com/doi/abs/10.1111/imr.13196
  66. https://pubmed.ncbi.nlm.nih.gov/9413890/
  67. https://www.jci.org/articles/view/97946
  68. https://europepmc.org/article/med/29670278
  69. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.10.165050
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC5706601/
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC8576416/
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC9819889/
  73. https://onlinelibrary.wiley.com/doi/10.1002/iid3.838
  74. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.848006/full
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC3150353/
  76. https://www.aps.anl.gov/APS-Science-Highlight/2022-01-11/finding-new-ways-to-treat-diabetes-and-other-inflammatory-diseases
  77. https://www.ahajournals.org/doi/10.1161/hq0302.105593
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC5647256/
  79. https://www.nature.com/articles/s41392-024-02049-y
  80. https://www.researchgate.net/publication/335040132_Phosphoinositide-3_kinase_gamma_regulates_caspase-1_activation_and_leukocyte_recruitment_in_acute_murine_gout
  81. https://pubmed.ncbi.nlm.nih.gov/26558820/
Add your contribution
Related Hubs
User Avatar
No comments yet.