Myeloid-derived growth factor promotes M2 macrophage polarization and attenuates Sjögren's syndrome via suppression of the CX3CL1/CX3CR1 axis

Front Immunol. 2024 Oct 21:15:1465938. doi: 10.3389/fimmu.2024.1465938. eCollection 2024.

Abstract

Introduction: Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by the infiltration of immune cells into the salivary glands. The re-establishment of salivary glands (SGs) function in pSS remains a clinical challenge. Myeloid-derived growth factor (MYDGF) has anti-inflammatory, immunomodulatory, and tissue-functional restorative abilities. However, its potential to restore SGs function during pSS has not yet been investigated.

Methods: Nonobese diabetic (NOD)/LtJ mice (pSS model) were intravenously administered with adeno-associated viruses carrying MYDGF at 11 weeks of age. Salivary flow rates were determined before and after treatment. Mice were killed 5 weeks after MYDGF treatment, and submandibular glands were collected for analyses of histological disease scores, inflammatory cell infiltration, PCR determination of genes, and Western blotting of functional proteins. Furthermore, mRNA sequencing and bioinformatics were used to predict the mechanism underlying the therapeutic effect of MYDGF.

Results: Treatment of NOD/LtJ mice with MYDGF alleviated pSS, as indicated by increased salivary flow rate, reduced lymphocyte infiltration, attenuated glandular inflammation, and enhanced AQP5 and NKCC1 expression. The gene expression levels of cytokines and chemokines, including Ccl12, Ccl3, Il1r1, Ccr2, Cx3cr1, Il7, Mmp2, Mmp14, Il1b, and Il7, significantly decreased after treatment with MYDGF, as determined by RNA sequencing. Meanwhile, MYDGF inhibits infiltration of macrophages (Mϕ) in SGs, induces polarization of M2ϕ, and suppresses C-X3C motif ligand 1 (CX3CL1)/C-X3C motif receptor 1 (CX3CR1) axis.

Conclusions: Our findings showed that MYDGF could revitalize the SGs function of pSS, inhibit infiltration of Mϕ, and promote M2ϕ polarization via suppression of the CX3CL1/CX3CR1 axis, which has implications for potential therapy for pSS.

Keywords: CX3CL1; CX3CR1; M2 macrophage polarization; Sjögren’s syndrome; myeloid-derived growth factor; salivary glands.

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1* / genetics
  • CX3C Chemokine Receptor 1* / metabolism
  • Chemokine CX3CL1* / genetics
  • Chemokine CX3CL1* / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Interleukins
  • Macrophage Activation / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred NOD*
  • Salivary Glands / immunology
  • Salivary Glands / metabolism
  • Salivary Glands / pathology
  • Signal Transduction
  • Sjogren's Syndrome* / immunology
  • Sjogren's Syndrome* / metabolism

Substances

  • CX3C Chemokine Receptor 1
  • Chemokine CX3CL1
  • Cx3cr1 protein, mouse
  • Cx3cl1 protein, mouse
  • interleukin-35, mouse
  • Interleukins

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Beijing Stomatological Hospital, Capital Medical University Young Scientist Program (YSP202204, YSP202008); the Beijing Municipal Natural Science Foundation (7232070), National Natural Science Foundation of China (82370940, 82001065); the Beijing Hospitals Authority Youth Programme (QML20211502); and the Beijing Talents Fund (2018000021469G284).