Mmm-derived lipid-associated membrane proteins activate IL-1β production through the NF-κB pathway via TLR2, MyD88, and IRAK4

Abstract

Mycoplasma mycoides subsp.mycoides (Mmm) is a pathogen that causes pneumonia, otitis media, and arthritis in young calves. Its pathogenesis is attributed in part to excessive immune responses. Mmm-derived lipid-associated membrane proteins (LAMPs) are potent inducers of the host innate immune system; however, interactions between Mmm-derived LAMPs as pathogenic agents, toll-like receptors (TLRs), and the signaling pathways responsible for activating inflammation and nuclear factor (NF)-κB have not been fully elucidated. Here, we analyzed the expression kinetics of interleukin (IL)-1β in Mmm-derived LAMP-stimulated embryonic bovine lung (EBL) cells and found that Mmm-derived LAMPs induced IL-1β expression. Subcellular localization analysis revealed the nuclear translocation of the NF-κB p65 subunit after EBL cells were stimulated with Mmm-derived LAMPs. Furthermore, a specific inhibitor assay demonstrated that NF-κB is required for Mmm-derived LAMP-induced IL-1β expression. Additionally, overexpression of TLR2, myeloid differentiation primary response gene 88 (MyD88), and IL-1 receptor-associated kinase 4 (IRAK4) increased IL-1β expression during LAMP stimulation, and TLR2-neutralizing antibodies reduced IL-1β expression in EBL cells during LAMP stimulation. Furthermore, LAMPs inhibited IL-1β expression following transfection with dominant-negative MyD88 and IRAK4 variants. These results suggested that Mmm-derived LAMPs activate IL-1β production through the NF-κB pathway via TLR2, MyD88, and IRAK4.

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells

“…As previously reported, miR-302b negatively regulates IL-1β production in monosodium urate crystal-induced inflammation by targeting IRAK4 ( Ma T. et al, 2018 ; Zhou et al, 2014 ), LPS targets TLRs (Toll-like receptors) and activates IRAK4, promoting nuclear translocation of p65 by upregulating phosphorylation of IKKβ/IκBα ( Wang Y. et al, 2017 ); thus, miR-302a may regulate IKKβ/IκBα by upstream IRAK4. We also predicted that there was a potential combining sequence between miR-302a and IRAK4 using TargetScan software ( Figure 6A ).…”

The Role of Lipoproteins in Mycoplasma-Mediated Immunomodulation

“…A key family of receptors that play an important role in recognizing, and inducing responses to Mycoplasmal lipoproteins are the Toll-Like Receptors (TLRs) that are key players in inflammatory responses upon infection ( Akira et al, 2001 ; Wang et al, 2017 ). Two of the most well-studied TLRs are TLR2 and TLR6, both of which are pivotal in recognizing Mycoplasmal Macrophage-Activating Lipopeptide-2 (MALP-2), with the absence of either TLR leading to a lack of recognition and macrophage activation ( Takeuchi et al, 2002 ).…”

Up-Regulation of miR-130b-3p Activates the PTEN/PI3K/AKT/NF-κB Pathway to Defense against Mycoplasma gallisepticum (HS Strain) Infection of Chicken

“…Mycoplasma is the simplest and smallest prokaryote widespread in nature, and is distinguished by the absence of a cell wall [ 1 ]. It can invade and survive in a wide range of eukaryotes, such as humans, plants, and domestic animals, leading to multiple diseases [ 2 , 3 , 4 ]. As one of the most important avian mycoplasma pathogens, Mycoplasma gallisepticum ( MG ) can cause chronic respiratory disease (CRD) characterized by chronic inflammation in the respiratory tract of chickens [ 5 ].…”