2. Academic Validation
  3. Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis

Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis

  • J Adv Res. 2023 May 9;S2090-1232(23)00127-3. doi: 10.1016/j.jare.2023.05.001.
Jun Zhao 1,  Yan Liu 2,  Xiaoyi Shi 2,  Junlong Dang 3,  Yu Liu 4,  Siwen Li 5,  Wei Cai 6,  Yuluan Hou 7,  Donglan Zeng 1,  Ye Chen 2,  Jia Yuan 7,  Yiding Xiong 1,  Wenbin Wu 8,  Peihong Cai 1,  Jingrong Chen 2,  Jianbo Sun 9,  Yimin Shao 9,  David D Brand 10,  Song Guo Zheng 11
Affiliations

Affiliations

  • 1 Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 2 Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 3 Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
  • 4 Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541000, China.
  • 5 School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
  • 6 Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 7 Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 8 Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 9 The first Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
  • 10 The Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN 38163, United States.
  • 11 Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China. Electronic address: [email protected].
PMID: 37169220 DOI: 10.1016/j.jare.2023.05.001
Abstract

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B×N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis.

Objectives: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis .

Methods: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B×N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments.

Results: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation.

Conclusion: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.

Keywords

PGE2-PKA-ERK axis; Rheumatoid arthritis; gingival-derived mesenchymal stem cells; neutrophil extracellular traps.

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