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Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of

Yongli Zhang1, Luna Ge1,2, Guanhua Song3

  • 1Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.

British Journal of Pharmacology
|October 19, 2021
PubMed
Abstract

Insights

Azithromycin demonstrates anti-inflammatory effects, offering potential as a rheumatoid arthritis treatment by targeting glucose-regulated protein 78 (GRP78). This macrolide antibiotic reduces inflammatory responses and arthritis severity in preclinical models.

Area of Science:

  • Immunology
  • Pharmacology
  • Molecular Biology

Background:

  • Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease.
  • Azithromycin, a macrolide antibiotic, possesses known anti-inflammatory properties.
  • The therapeutic potential of azithromycin in RA requires further substantiation.

Purpose of the Study:

  • To investigate the anti-inflammatory and anti-arthritic effects of azithromycin.
  • To identify the molecular targets and mechanisms underlying azithromycin's action in RA.
  • To evaluate azithromycin as a potential treatment for rheumatoid arthritis.

Main Methods:

  • RNA sequencing for gene expression profiling.
  • In vitro assays using rheumatoid arthritis fibroblast-like synoviocytes.
  • In vivo collagen-induced arthritis model in DBA/1 mice.
  • Biophysical assays (DARTs, proteomics, CETSA) to characterize azithromycin-GRP78 binding.

Main Results:

  • Azithromycin reduced pro-inflammatory factors, cell migration, invasion, and chemoattraction in RA synoviocytes.
  • Azithromycin ameliorated collagen-induced arthritis severity, comparable to etanercept.
  • GRP78 was identified as a novel direct target of azithromycin.
  • Azithromycin's anti-arthritic activity is mediated by GRP78 inhibition, impacting the unfolded protein response and cholesterol/lipid biosynthesis pathways.

Conclusions:

  • Azithromycin exhibits significant anti-arthritic properties.
  • Targeting GRP78 with azithromycin represents a novel therapeutic strategy for rheumatoid arthritis.
  • Azithromycin holds promise as a treatment for rheumatoid arthritis.
Keywords:
GRP78azithromycinfibroblastsrheumatoid arthritisunfolded protein response

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