Spinal Microglial TLR7 Activation Drives Hyperalgesia in a Lupus Mouse Model via Upregulation of IL-1β, IL-18, and Cav2.2 and Enhanced Glutamatergic Synaptic Activity

Sep 30, 2026

Uploaded by James

Systemic lupus erythematosus (SLE) patients frequently experience chronic pain driven by inadequate analgesic efficacy and safety. This study examines how spinal TLR7 contributes to chronic pain in female MRL/lpr mice, a lupus-prone model. Starting at 11 weeks, MRL/lpr mice show progressive thermal hypersensitivity, plateauing by 14–16 weeks, alongside increased TLR7 expression in the spinal dorsal horn microglia. Blocking spinal TLR7 reduces hypersensitivity, whereas agonist activation induces it in controls and reproduces molecular, synaptic, and cellular alterations, including glial activation and elevated IL-1β/IL-18, Cav2.2 upregulation, enhanced glutamatergic activity, and increased neuronal activation.

LanguageEnglish

CategoryHealthcare

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Article Spinal Microglial TLR7 Activation Drives Hyperalgesia in a Lupus Mouse Model via Upregulation of IL-1β, IL-18, and Cav2.2 and Enhanced Glutamatergic Synaptic Activity Saumya Bipin 1, Viacheslav Viatchenko-Karpinski 2, Catherine Li 1, Sujin Lim 1 and Han-Rong Weng 1,2, * Academic Editor: James Grau Received: 20 November 2025 Revised: 16 December 2025 Accepted: 19 December 2025 Published: 22 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Basic Sciences, California Northstate University College of Medicine, 9700 W Taron Drive, Elk Grove, CA 95757, USA; [saumya.bipin@cnsu.edu](saumya.bipin@cnsu.edu) (S.B.); [catherine.li11708@cnsu.edu](catherine.li11708@cnsu.edu) (C.L.); [sujin.lim11464@cnsu.edu](sujin.lim11464@cnsu.edu) (S.L.) 2 Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA; [viatc001@umn.edu](viatc001@umn.edu) * [Correspondence: han-rong.weng@cnsu.edu](Correspondence: han-rong.weng@cnsu.edu); Tel.: +1-916-686-7897 Highlights What is the main finding? • Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due to the insufficient efficacy and safety profile of currently available analgesics. In this study, we revealed that TLR7 signaling activity is elevated in the spinal dorsal horn in lupus mice with thermal hyperalgesia. TLR7 activation drives molecular, synaptic, cellular, and pain phenotype alterations in lupus mice. What is the implication of the main finding? • Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE. Abstract Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due toa lack of effective and safe analgesics. In this study, we investigated the role of spinal TLR7 in the pathogenesis of chronic pain using female MRL lupus prone (MRL/lpr) mice, a SLE mouse model. We found that from 11 weeks of age, MRL/lpr mice exhibited thermal hypersensitivity in the hind paw, which reached plateau between 14 and 16 weeks. MRL/lpr mice with thermal hypersensitivity had increased expression of TLR7 in the spinal dorsal horn. TLR7 was located in microglia in this region. Intrathecal administration of a TLR7 antagonist attenuated the thermal hypersensitivity in MRL/lpr mice, while administration of the TLR7 agonist induced thermal hypersensitivity in control mice. Pharmacological activation of spinal TLR7 in control mice recapitulated molecular, synaptic, and cellular changes in the spinal dorsal horn of MRL/lpr mice with thermal hyperalgesia. These alterations included activation of microglia and astrocytes, increased production of IL-1β and IL-18, upregulated expression of N-type voltage-gated calcium channels (Cav2.2), enhanced glutamatergic synaptic activity, and elevated neuronal activation. Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE. Keywords: nociception; neuroinflammation; glial neuronal interaction; synaptic; EPSC 1. Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread inflammation and multi-organ involvement. Among its many manifestations, chronic pain is a debilitating symptom that affects a substantial proportion of patients, severely diminishing their quality of life [1–3] . Understanding the cellular and molecular mechanisms underlying SLE-induced chronic pain is therefore essential for developing novel therapeutic strategies to alleviate this condition. The MRL/lpr lupus-prone mouse (Jackson Laboratory) is one of the most commonly used models of SLE [4–7], as it spontaneously develops key pathological features resembling human SLE. Similarly to S

FAQs

What role does spinal TLR7 play in lupus-related chronic pain in the study?

Spinal TLR7 signaling is elevated in the spinal dorsal horn of lupus mice with thermal hyperalgesia, and it drives molecular, synaptic, cellular, and pain phenotype changes.

How did inhibiting or activating TLR7 affect thermal hypersensitivity?

Intrathecal administration of a TLR7 antagonist attenuated thermal hypersensitivity in MRL/lpr mice, while administration of a TLR7 agonist induced thermal hypersensitivity in control mice.

Which downstream molecular and cellular changes were observed with TLR7 activation?

TLR7 activation increased microglia and astrocyte activation, raised IL-1β and IL-18 production, upregulated Cav2.2, enhanced glutamatergic synaptic activity, and elevated neuronal activation.

Sep 30, 2026

Uploaded by James