20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

Abstract

Leukotriene B4 (LTB4) plays a prominent role in innate immunity as it induces phagocyte recruitment, the release of antimicrobial effectors, and as it potentiates the ingestion and killing of pathogens. In humans, LTB4 has a short half‐life and is rapidly metabolized by leukocytes, notably into 20‐OH‐ and 20‐COOH‐LTB4 by neutrophils. Although these LTB4 metabolites bind to the BLT1 receptor with high affinity, they activate neutrophils to a much lower extent than LTB4. We thus postulated that LTB4 metabolites could dampen BLT1‐mediated responses, therefore limiting the impact of LTB4 on human neutrophil functions. We found that 20‐OH‐LTB4 and 20‐COOH‐LTB4 inhibited all of the LTB4‐mediated neutrophil responses we tested (migration, degranulation, leukotriene biosynthesis). The potencies of the different compounds at inhibiting LTB4‐mediated responses were 20‐OH‐LTB4 = CP 105,696 (BLT1 antagonist) > > 20‐COOH‐LTB4 ≥ resolvin E1 (RVE1). In contrast, the fMLP‐ and IL‐8‐mediated responses we tested were not affected by the LTB4 metabolites or RVE1. 20‐OH‐LTB4 and 20‐COOH‐LTB4 also inhibited the LTB4‐mediated migration of human eosinophils but not that induced by 5‐KETE. Moreover, using 20‐COOH‐LTB4, LTB4, and LTB4‐alkyne, we show that LTB4 is a chemotactic, rather than a chemokinetic factor for both human neutrophils and eosinophils. In conclusion, our data indicate that LTB4 metabolites and RVE1 act as natural inhibitors of LTB4‐mediated responses. Thus, preventing LTB4 ω‐oxidation might result in increased innate immunity and granulocyte functions.

Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites

“…Conceptually, this might diminish the effectiveness of LTB4 at promoting its host-defense related functions, as we recently published (46). Interestingly, there was a trend toward an inverse correlation between LTE4 and EXE4, indicating that these cysteinyl-LTs are likely coming from different cellular sources.…”

“…While LTB 4 has previously been shown to stimulate host defense (41), notably during viral infections, the ω-LTB 4 /LTB 4 ratio of 2.84 we observed is more reminiscent of what is found in cystic fibrosis and severely burned patients, two conditions in which infections are not well controlled (42-45). Conceptually, this might diminish the effectiveness of LTB 4 at promoting its host-defense related functions, as we recently published (46). Interestingly, there was a trend toward an inverse correlation between LTE 4 and EXE 4, indicating that these cysteinyl-LTs are likely coming from different cellular sources.…”

Gram-Negative Bacteria Salmonella typhimurium Boost Leukotriene Synthesis Induced by Chemoattractant fMLP to Stimulate Neutrophil Swarming

“…PMNLs after phagocytosis of bacteria showed a partially or completely suppressed respiratory burst ( Grone et al, 1992 ). 20-OH- and 20-COOH-LTB 4 bind to the BLT1 receptor with high affinity but activate neutrophils to a much lower extent than LTB 4 ( Archambault et al, 2019 ), so ω-OH-LTB 4 and ω-COOH-LTB 4 act as natural inhibitors of LTB 4 -mediated responses. Thus, preventing LTB 4 ω-oxidation might result in increased innate immunity and granulocyte functions.…”

Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners

“…Lipids were extracted with solid phase extraction (SPE) cartridges (Strata-X Polymeric Reversed Phase, 60 mg/3 mL, Phenomenex, Torrance, CA, USA), as we previously described [ 16 ]. In brief, the denatured samples were centrifuged to eliminate cell debris and diluted with water to obtain a final MeOH concentration of 10% and acidified (pH 3) with acetic acid.…”