Leukotriene B4 Enhances NOD2-Dependent Innate Response against Influenza Virus Infection

Abstract

Leukotriene B4 (LTB4), a central mediator of inflammation, is well known for its chemoattractant properties on effectors cells of the immune system. LTB4 also has the ability to control microbial infection by improving host innate defenses through the release of antimicrobial peptides and modulation of intracellular Toll-like receptors (TLRs) expression in response to agonist challenge. In this report, we provide evidences that LTB4 acts on nucleotide-binging oligomerization domain 2 (NOD2) pathway to enhance immune response against influenza A infection. Infected mice receiving LTB4 show improved survival, lung architecture and reduced lung viral loads as compared to placebo-treated animals. NOD2 and its downstream adaptor protein IPS–1 have been found to be essential for LTB4-mediated effects against IAV infection, as absence of NOD2 or IPS–1 diminished its capacity to control viral infection. Treatment of IAV-infected mice with LTB4 induces an increased activation of IPS-1-IRF3 axis leading to an enhanced production of IFNβ in lungs of infected mice. LTB4 also has the ability to act on the RICK-NF-κB axis since administration of LTB4 to mice challenged with MDP markedly increases the secretion of IL–6 and TNFα in lungs of mice. TAK1 appears to be essential to the action of LTB4 on NOD2 pathway since pretreatment of MEFs with TAK1 inhibitor prior stimulation with IAV or MDP strongly abrogated the potentiating effects of LTB4 on both IFNβ and cytokine secretion. Together, our results demonstrate that LTB4, through its ability to activate TAK1, potentiates both IPS–1 and RICK axis of the NOD2 pathway to improve host innate responses.

RNA Sequencing of H3N2 Influenza Virus-Infected Human Nasal Epithelial Cells from Multiple Subjects Reveals Molecular Pathways Associated with Tissue Injury and Complications

“…The genes in the pathway may be analyzed for their immunomodulatory activity and whether their expression is beneficial to the virus (immune evasion) or the host (preventing cytokine storm). In addition, the infected hNECs also revealed modified responses associated with fatty acid, with many lipid signaling molecules such as leukotrienes that mediate antiviral responses and subsequent inflammation of the airway [51,52]. Such modified responses may also determine the afforded in the airway and the severity of airway inflammation and damage.…”

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

“…The roles of LTB 4 in host defense are well established 3,36 and its administration in humans and animals yielded promising results for its utilization as a booster of innate immunity. [6][7][8][9][10]33,37 However, LTB 4 has a short half-life in neutrophils and is rapidly oxidized into 20-OH-LTB 4 , then into 20-COOH-LTB 4 . 11 20-OH-LTB 4 and 20-COOH-LTB 4 are often considered as inactive given that they are less effective at inducing neutrophil functions, [15][16][17][18][19][20][21][22][23]33 some reports even showing that 20-OH-LTB 4 administration downregulates neutrophilic inflammation.…”

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

“…Once described as an intracellular PRR exclusively involved in bacterial infections, several studies have suggested that NOD2 has a broader than expected role in the innate immune system193738. Using L. sigmodontis , the murine model for human tissue invasive filarial infections, we provide the first evidence that NOD2 is also essential for the early immune response against incoming infectious larvae during infection with filarial nematodes.…”