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Azithromycin alleviates the severity of rheumatoid arthritis via targeting UPR component GRP78
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  • Yongli Zhang,
  • Luna Ge,
  • Guanhua Song,
  • Ruojia Zhang,
  • Shufeng Li,
  • Haojun Shi,
  • Hongchang Zhang,
  • Yi Li,
  • Jihong Pan,
  • Lin Wang,
  • Jinxiang Han
Yongli Zhang
Shandong First Medical University
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Luna Ge
First Affiliated Hospital of Shandong First Medical University
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Guanhua Song
Shandong First Medical University
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Ruojia Zhang
Shandong First Medical University
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Shufeng Li
First Affiliated Hospital of Shandong First Medical University
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Haojun Shi
Henan University of Traditional Chinese Medicine
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Hongchang Zhang
Shandong First Medical University
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Yi Li
Shandong Provincial Hospital
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Jihong Pan
First Affiliated Hospital of Shandong First Medical University
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Lin Wang
First Affiliated Hospital of Shandong First Medical University
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Jinxiang Han
First Affiliated Hospital of Shandong First Medical University
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Abstract

Background and Purpose: Azithromycin (AZM) is a macrolide antibiotic with well-described anti-inflammatory properties. This study aimed to substantiate its treatment potential in rheumatoid arthritis (RA). Experimental Approach: Gene expression profiles were collected by RNA-sequencing and the effects of AZM were assessed in functional assays. In vitro and vivo assays for examining the blockade of glucose-regulated protein 78 (GRP78) actions by AZM: assays for defining the anti-inflammatory activity of AZM using fibroblast-like synoviocytes (FLSs) from RA patients as well as collagen-induced arthritis (CIA) in DBA/1 mice. Identification and characterization of the binding of AZM to GRP78 using drug affability responsive target stability assay, proteomics and cellular thermal shift assay. Detect AZM inhibition of GRP78 and dependence of AZM’s anti-arthritis activity on GRP78. Key Results: AZM reduced pro-inflammatory factor production, cell migration, invasion and chemo-attractive potential, enhanced apoptosis, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. AZM ameliorated the severity of CIA lesions. Transcriptional analyses implied that AZM treatment causes impairments in signaling cascades associated with cholesterol and lipid biosynthetic process. GRP78 was isolated as a novel target of AZM. AZM-mediated activation of unfolded protein response (UPR) via inhibiting GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (CHOP), but also for activation of sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic process. Further, deletion of GRP78 abolished AZM’s anti-arthritis activity. Conclusion and Implications: These findings confirmed that AZM is an anti-arthritis therapeutic drug for RA treatment.

Peer review status:UNDER REVIEW

29 Dec 2020Submitted to British Journal of Pharmacology
30 Dec 2020Submission Checks Completed
30 Dec 2020Assigned to Editor
20 Jan 2021Reviewer(s) Assigned
16 Feb 2021Review(s) Completed, Editorial Evaluation Pending
01 Mar 2021Editorial Decision: Revise Minor
30 May 20211st Revision Received
01 Jun 2021Submission Checks Completed
01 Jun 2021Assigned to Editor
08 Jun 2021Reviewer(s) Assigned