Nucleotide-binding oligomerization domain 1/Toll-like receptor 4 co-engagement promotes non-specific immune response against K562 cancer cells

Guzelj, Samo (author), Jakopin, Žiga (author)

Nucleotide-binding oligomerization domain 1 (NOD1) receptor and Toll-like receptor 4 (TLR4) belong to the family of pattern recognition receptors. Interactions between these receptors profoundly shape the innate immune responses. We previously demonstrated that co-stimulation of peripheral blood mononuclear cells (PBMCs) with D-glutamyl-meso-diaminopimelic acid (iE-DAP)-based NOD1 agonists and lipopolysaccharide (LPS), a TLR4 agonist, synergistically increased the cytokine production. Herein, we postulate that stimulation of NOD1 alone or a combined stimulation of NOD1 and TLR4 could also strengthen PBMC-mediated cytotoxicity against cancer cells. Initially, an in-house library of iE-DAP analogs was screened for NOD1 agonist activity to establish their potency in HEK-Blue NOD1 cells. Next, we showed that our most potent NOD1 agonist SZZ-38 markedly enhanced the LPS-induced cytokine secretion from PBMCs, in addition to PBMC- and natural killer (NK) cell-mediated killing of K562 cancer cells. Activation marker analysis revealed that the frequencies of CD69$^+$, CD107a$^+$, and IFN-γ$^+$ NK cells are significantly upregulated following NOD1/TLR4 co-stimulation. Of note, SZZ-38 also enhanced the IFN-γ-induced PBMC cytotoxicity. Overall, our findings provide further insight into how co-engagement of two pathways boosts the non-specific immune response and attest to the importance of such interplay between NOD1 and TLR4.

• Language: English
• Keywords: NOD1 agonist, TLR4 agonist, LPS, synergy, cytolytic activity, PBMC, NK cells, K562
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 12 str.
• Numbering: Vol. 13, art. 920928
• PID: 20.500.12556/RUL-138682-14c3a078-d0fe-62c5-3f1a-393bbe4eb580
• UDC: 615.4:54:616-097
• ISSN on article: 1663-9812
• DOI: 10.3389/fphar.2022.920928
• COBISS.SI-ID: 117623555
• Publication date in RUL: 09.08.2022

Record is a part of a journal

• Title: Frontiers in pharmacology
• Shortened title: Front Pharmacol
• Publisher: Frontiers Media
• ISSN: 1663-9812
• COBISS.SI-ID: 29551833

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: agonist NOD1, agonist TLR4, sinergija, citolitična aktivnost, celice NK, farmacevtska kemija, imunski odziv