# 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

## TL;DR

This study shows that TLR7 activation in spinal microglia contributes to chronic pain in a lupus mouse model, suggesting new treatment targets.

## Contribution

The study identifies TLR7 as a key driver of chronic pain in lupus through specific molecular and synaptic changes.

## Key findings

- TLR7 activation in spinal microglia causes thermal hypersensitivity in lupus mice.
- Blocking TLR7 reduces pain and reverses synaptic and inflammatory changes.
- TLR7 activation increases IL-1β, IL-18, and Cav2.2, enhancing glutamatergic activity.

## Abstract

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.

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.

Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE.

Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due to a 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.