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

Sep 30, 2026

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Toll-like receptor 2 (TLR2) plays a critical role in the central nervous system across neurological and neurodegenerative disorders, making its function essential to clarify. This study examines neuronal responses to individual TLR2 ligands, showing increased cytokine expression and lipoteichoic acid (LTA)-dependent elevation of lactate dehydrogenase (LDH). LTA also reduces Ca2+ oscillation peak amplitude. The ROS blocker MnTBAP suppresses LTA-induced cell death without altering Ca2+ spike peak amplitude, whereas Pam3CSK4 increases Ca2+ peaks via TNFα signaling.

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Cellular and Molecular Neurobiology (2026) 46:4 [https://doi.org/10.1007/s10571-025-01632-3](https://doi.org/10.1007/s10571-025-01632-3) ORIGINAL RESEARCH Diverse Effects of Various Toll-Like Receptor 2 Ligands on Neuronal Activity and Cell Death Futa Sato1,2 · Satoshi Hachimura1 Received: 1 May 2025 / Accepted: 3 November 2025 © The Author(s) 2025 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. 􀀍 Satoshi Hachimura [ahachi@g.ecc.u-tokyo.ac.jp](ahachi@g.ecc.u-tokyo.ac.jp) Futa Sato [sato.futa@otsuka.jp](sato.futa@otsuka.jp) 1 Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan 2 Department of CNS Research, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima 771-0192, Japan 1 3 Graphical Abstract 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. Keywords TLR2 · Neuron · Cell death · Calcium oscillation Abbreviations BSA CNS DIV FADD GFAP HBSS ICAM IL JAK LDH LPS LTAMyD88 Nav NMDAP3C PAMPs/DAMPs PBS PFA ROS PRR TRPV1 Bovine serum albumin Central nervous system Days in vitro Fas-associated protein with death domain Glial fibrillary acidic protein Hanks’balanced salts solution Intercellular adhesion molecule 1 Interleukin Janus kinase Lactate dehydrogenase Lipopolysaccharide Lipoteichoic acid Myeloid differentiation factor 88 Voltage-gated sodium channel N-methyl-D-aspartate Pam3CSK4 Pathogen/Damage-associated molecular patterns Phosphate-buffered saline Paraformaldehyde Reactive oxygen species Pattern recognition receptor Transient receptor potential vanilloid subfamily member 1 TNFα Tumor necrosis factor alpha TUBB3 Class III beta-tubulin TLR Toll-like receptor ZA ZymosanA Introduction Many pathogens possess common pathogen/damage-associated molecular patterns (PAMPs/DAMPs), and immune cells recognize these PAMPs/DAMPs through pattern recognition receptors (PRRs) (Donnelly et al. 2020) . TLRs, which are a type of PRR, play pivotal roles in the immune response against bacterial infections (Fitzgerald and Kagan 2020; Li and Wu 2021) . The involvement ofTLR signaling has been reported in relation to infections by viruses and bacteria in the CNS (Aravalli et al. 2007) . It is well known that TLR2 recognizes a variety of bacterial lipopeptides, such as LTA (Schwandner et al. 1999), synthetic lipoprotein structure P3C (Funderburg et al. 2011), and bacterial lipopolysaccharide (LPS) (Kirschning et al. 1998) . Previous studies have rep

FAQs

What was the main goal of this study on TLR2?

To investigate how individual TLR2 ligands influence neuronal responses, including cytokine expression, calcium dynamics, and cell death.

How did lipoteichoic acid (LTA) affect neuronal activity and cell death?

LTA increased cytokine-related expression and elevated LDH, while decreasing the peak amplitude of Ca2+ oscillations and inducing cell death.

What did MnTBAP and Pam3CSK4 reveal about the mechanisms involved?

MnTBAP inhibited LTA-induced cell death through ROS signaling without changing Ca2+ spike peak amplitude, while Pam3CSK4 increased the number of Ca2+ peaks and this effect was blocked by a TNFα signaling inhibitor.

Sep 30, 2026

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