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

Introduction Primary Sj & ouml;gren 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 (M phi) in SGs, induces polarization of M2 phi, 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 M phi, and promote M2 phi polarization via suppression of the CX3CL1/CX3CR1 axis, which has implications for potential therapy for pSS.