IL-38 and IL-36 Target Autophagy for Regulating Synoviocyte Proliferation, Migration, and Invasion in Rheumatoid Arthritis.

Zhe Hao,Yi Liu,Wen-Jun Tu

doi:10.1155/2021/7933453

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease leading to severe joint damage and disability. Fibroblast-like synoviocytes (FLSs) mostly contribute to the joint inflammation and destruction in RA through distinct mechanisms. However, little is known about newly discovered interleukin- (IL-) 36 and IL-38 involving in the pathology of RA. Here, we assessed the effect of IL-36 and IL-38 on RA-FLS function using IL-36 and IL-38 overexpression plasmids. We found that IL-36 inhibited synoviocytes proliferation while IL-38 showed an opposite influence. Furthermore, IL-36 and IL-38 significantly sequestered or accelerated RA-FLS migration and invasion capacity, respectively. Mechanically, IL-36 and IL-38 targeted autophagy for RA-FLS modulation. Using autophagy inhibitor 3-MA and inducer compound rapamycin, we found that autophagy negatively regulated the survival, migration, and invasion of synovial cells. Based on these results, IL-38 in combination with autophagy inhibitor 3-MA treatment demonstrated the strongest blockage of the above three activities of RA-FLS, and IL-38 overexpression reversed rapamycin-inhibited cell proliferation, migration, and invasion. Moreover, injection of IL-36 can improve the symptoms of RA in a rat model of RA. Taken together, we conclude that IL-38 and IL-36 target autophagy for regulating synoviocyte proliferation, migration, and invasion in RA.

Highlights

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune arthritides characterized by immunoglobulin G and citrullinated protein-specific autoantibodies induced synovial inflammation and hyperplasia, leading to cartilage damage and bone destruction [1]
We want to determine the effect of IL-36 and IL-38 on the proliferation of fibroblastlike synoviocytes (FLSs) in RA pathology
EdU cell proliferation assay was performed to evaluate the proliferation of SW982 cells transfected with IL-36 or IL-38 expression plasmids

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune arthritides characterized by immunoglobulin G and citrullinated protein-specific autoantibodies induced synovial inflammation and hyperplasia, leading to cartilage damage and bone destruction [1]. It is related to systemic disorders such as cardiovascular, pulmonary, and skeletal dysfunction, among which accompanied cardiovascular disease ascribes to the most common cause of mortality of RA patients [2]. The increasing number of FLS contributes to the transformation of synovial lining into invasive pannus, which can migrate between joints and is directly responsible for cartilage and bone damage [7]. Instead of focusing on altering proinflammation cytokines and the immune signaling, targeting RA-FLS to deactivate its autonomous and aggressive phenotypes can be promising strategies for RA therapy

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Conclusion