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Inhibition of Spinal Interleukin-33 Attenuates Peripheral Inflammation and Hyperalgesia in Experimental Arthritis

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Abstract

Accumulating evidence indicates that the continuous and intense nociceptive from inflamed tissue may increase the excitability of spinal dorsal horn neurons, which can signal back and modulate peripheral inflammation. Previous studies have demonstrated that spinal interleukin (IL)-33 contributes to the hyperexcitability of spinal dorsal horn neurons. This study was undertaken to investigate whether spinal IL-33 can also influence a peripheral inflammatory response in a rat model of arthritis. Lentivirus-delivered short hairpin RNA targeting IL-33 (LV-shIL-33) was constructed for gene silencing. Rats with adjuvant-induced arthritis (AIA) were injected intrathecally with LV-shIL-33 3 days before the complete Freund’s adjuvant (CFA) injection. During an observation period of 21 days, pain-related behavior and inflammation were assessed. In addition, the expression of spinal proinflammatory cytokines and the activation of spinal extracellular signal–regulated kinase (ERK) and nuclear factor-κB (NF-κB) pathways were evaluated on 9 days after CFA treatment. The existence of tissue injury or inflammation in rats with AIA resulted in the upregulation of spinal IL-33, which is predominantly expressed in neurons, astrocytes, and oligodendrocytes. Intrathecal administration of LV-shIL-33 significantly alleviated hyperalgesia, paw swelling, and joint destruction, and attenuated the expression of proinflammatory cytokines [IL-6, IL-1β, and tumor necrosis factor-α (TNF-α)], as well as the activation of ERK and NF-κB/p65 in the spinal cord. Our data suggest that spinal IL-33 contributes to the development of both peripheral inflammation and hyperalgesia. Thus, interference with IL-33 at the spinal level might represent a novel therapeutic target for painful inflammatory disorders.

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Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

IL-33:

Interleukin-33

CFA:

Complete Freund’s adjuvant

HPA:

Hypothalamic-pituitary-adrenal

AIA:

Adjuvant-induced arthritis

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

TNF-α:

Tumor necrosis factor-α

NF-κB:

Nuclear factor-κB

ERK:

Extracellular signal-regulated kinase

JNK:

C-Jun N-terminal kinase

GFAP:

Glial fibrillary acidic protein

NeuN:

Neuronal-specific nuclear protein

siRNAs:

Small interfering RNAs

RA:

Rheumatoid arthritis

CXCL-8:

C-X-C motif chemokine ligand 8

MMP-3:

Matrix metalloproteinase-3

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81600976) and the Natural Science Foundation of Hunan Province, China (Grant No. 2018JJ6138).

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Author notes

  1. Si-Jian Huang and Lu-Yao Zhou contributed equally.

Authors and Affiliations

  1. Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Si-Jian Huang, Lu-Yao Zhou, Fei Ren, Wang-Yuan Zou, Jian-Qin Yan & Jian-Gang Luo

  2. Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Si-Jian Huang

  3. Department of Anesthesiology, The Fifth Hospital Afflicted Sun-Yat Sen University, Zhuhai City, Guangdong, People’s Republic of China

    Lu-Yao Zhou

  4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Jian-Gang Luo

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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Luo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design, Luo, Yan; acquisition of data, Huang, Zhou, Luo; analysis and interpretation of data, Zhou.

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Correspondence to Jian-Gang Luo.

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All the animal studies were approved by the Animal Ethics Committee of Central South University (No. 201603359)and complied with the ethical guidelines of the International Association for the Study of Pain (IASP).

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Huang, SJ., Zhou, LY., Ren, F. et al. Inhibition of Spinal Interleukin-33 Attenuates Peripheral Inflammation and Hyperalgesia in Experimental Arthritis. Mol Neurobiol 59, 2246–2257 (2022). https://doi.org/10.1007/s12035-022-02754-1

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