Tu92 - TLR-4 Agonist Induces IFN-gamma Production Selectively in Pro-inflammatory Human M1 Macrophages Through the PI3K-mTOR and JNK-MAPK Activated p70S6K Pathway

Tuesday, June 21, 2022

6:15 PM – 7:45 PM PT

Presenting Author(s)

AK

Ashok Kumar, n/a

Professor
Children's Hospital of Eastern Ontario, U. Ottawa
Ottawa, Ontario, Canada

Co-Author(s)

NG

Niranjala Gajnayaka, n/a

Children's Hospital of Eastern Ontario, U. Ottawa
Ottawa, Ontario, Canada
HA

Hamza Ali, n/a

Children's Hospital of Eastern Ontario, U. Ottawa
Ottawa, Ontario, Canada

IFN-g, a pro-inflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-g production by murine macrophages, IFN-g production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-g, and IL-12 and IL-18-stimulated monocyte-derived macrophages (MDM-M0) produce significant levels of IFN-g. Further stimulation of IL-12/IL-18-primed macrophages or M1 macrophages with agonists for Toll-like receptors (TLR)-2, TLR-3 or TLR-4 significantly enhanced IFN-g production in contrast to the similarly stimulated M0, M2a, M2b and M2c macrophages. Similarly, M1 macrophages generated from COVID-19-infected patient’s macrophages produced IFN-g that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-g production suggesting that differentiation with IFN-g plays a key role in IFN-g induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4-induced IFN-g production in M1 macrophages. Our results show that TLR-4-induced IFN-g production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of phosphoinositide-3-kinase (PI3K), the mammalian target of rapamycin complex-1/2 (mTORC-1/2) and the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) p</span>athways. These results suggest that M1-derived IFN-g may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC-1/2, PI3K and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.