Diverse Effects of Various Toll-Like Receptor 2 Ligands on Neuronal Activity and Cell Death

TL;DR

This study shows that different TLR2 ligands affect neurons in distinct ways, influencing calcium activity and cell death through various signaling pathways.

Contribution

The study reveals distinct effects of TLR2 ligands on neuronal activity and death via TLR1-TLR2 and TLR2-TLR6 signaling.

Findings

LTA stimulation reduced Ca2+ peak amplitude and induced cell death via ROS signaling.

P3C stimulation increased Ca2+ peaks through a TNFα-dependent pathway.

TLR2 ligands elicit diverse effects on primary cortical cells depending on their signaling partners.

Abstract

The role of Toll-like receptor 2 (TLR2) in the central nervous system (CNS) is critical in several conditions including neurological disorders such as pain, and neurodegenerative disorders such as Parkinson’s disease. Therefore, understanding TLR2 function in the CNS is of considerable importance. In this study, we investigated neuronal responses to individual TLR2 ligands. The expression levels of cytokines increased in the culture in the presence of TLR2 ligands. Additionally, increased lactate dehydrogenase (LDH) was noted during lipoteichoic acid (LTA) stimulation. During LTA stimulation, a decrease in the peak amplitude of Ca2 + oscillations was observed. MnTBAP, which is a reactive oxygen species (ROS) blocker, inhibited the LTA-induced cell death but had no effect on the peak amplitude of the Ca2 + spike. Conversely, Pam3CSK4 (P3C) stimulation increased the number of Ca2 + peaks, which was inhibited by a tumor necrosis factor alpha (TNFα) signaling inhibitor. Our study revealed that several TLR2 ligands, each with different specificities, elicited diverse responses in primary cortical cells. In conclusion, TLR1-TLR2 and TLR2-TLR6 signaling reduces the peak amplitude and induces cell death, and TLR1-TLR2 signaling enhances Ca2 + dynamics via a TNFα pathway.

P3C stimulation increased the number of Ca2+ peaks, which was inhibited by a TNFα signaling inhibitor. LTA stimulation decreased the amplitude of Ca2+ peaks, and induced cell death via ROS signaling.

P3C stimulation increased the number of Ca2+ peaks, which was inhibited by a TNFα signaling inhibitor. LTA stimulation decreased the amplitude of Ca2+ peaks, and induced cell death via ROS signaling.

The online version contains supplementary material available at 10.1007/s10571-025-01632-3.

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