Transcription factor Fli-1 impacts the expression of CXCL13 and regulates immune cell infiltration into the kidney in MRL/lpr mouse

• Published in: Lupus science & medicine Vol. 10; no. 1; p. e000870
• Main Authors: Sato, Shuzo, Zhang, Xian K, Matsuoka, Naoki, Sumichika, Yuya, Saito, Kenji, Yoshida, Shuhei, Matsumoto, Haruki, Temmoku, Jumpei, Fujita, Yuya, Asano, Tomoyuki, Migita, Kiyoshi
• Format: Journal Article
• Language: English
• Published: England Lupus Foundation of America 01.04.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Alzheimer's disease; Animal Models; Animals; Antibodies; Autoimmune diseases; Chemokines; Chemokines - genetics; Chemokines - metabolism; Cytokines; Dehydrogenases; Humans; Inflammation; Kidney - metabolism; Kidneys; Leukemia; Ligands; Lupus; Lupus Erythematosus, Systemic - pathology; Lupus Nephritis; Lymphoma; Mice; Mice, Inbred MRL lpr; Pathogenesis; R&D; Research & development; RNA, Messenger - metabolism; SOXC Transcription Factors - metabolism; Transcription factors; Transcription Factors - metabolism; New Zealand; United States > US; Japan; Lupus Nephritis; Inflammation; Chemokines
• ISSN: 2053-8790; 2053-8790
• DOI: 10.1136/lupus-2022-000870

ObjectiveFriend leukaemia virus integration 1 (Fli-1) regulates chemokine/cytokine expression and thus plays an important role in the development of lupus nephritis. Chemokine CXC ligand 13 (CXCL13) is a chemokine that promotes the formation of ectopic lymphoid structures and has been reported to be associated with the pathogenesis of lupus nephritis. The relationship between Fli-1 and CXCL13 is unknown. This study aims to elucidate whether Fli-1 impacts CXCL13 expression and contributes to the progression of lupus-like nephritis in adult MRL/lpr mouse.MethodsSerum CXCL13 levels were measured in adult wild-type (WT) MRL/lpr mice and Fli-1 heterozygote knockout (Fli-1+/−) MRL/lpr mice (4 months old or older) using ELISA. Renal mRNA expression (CXCL13 and related molecules) was measured using real-time PCR method. Kidneys were removed, stained and evaluated using a pathology scoring system. The grade of CXCL13 or CXC-chemokine receptor type 5 (CXCR5)-positive immune cell infiltration into the kidney was evaluated using immunostaining with anti-CXCL13 or anti-CXCR5 antibodies. We also used immunofluorescence staining with CXCL13- and CD11b-specific antibodies to detect the infiltration of CXCL13/CD11b double-positive immune cells.ResultsSerum CXCL13 levels in Fli-1+/− MRL/lpr mice were significantly lower than that in WT MRL/lpr mice (545.5 and 960.5 pg/mL, p=0.02). Renal expression of CXCL13 mRNA and SRY-related HMG box4 (Sox4) (an important factor for B-cell development) levels were significantly lower in Fli-1+/− MRL/lpr mice. Renal histology scores in WT MRL/lpr mice revealed significantly increased glomerular inflammation. Despite similar interstitial immune cell infiltration into the kidney, the number of CXCL13- and CXCR5-positive cells was significantly lower in Fli-1+/− MRL/lpr mice than in WT mice. Furthermore, immunofluorescence staining revealed that Fli-1+/-MRL/lpr mice had significantly fewer CXCL13/CD11b double-positive immune cells.ConclusionFli-1 regulates renal Sox4 mRNA expression and infiltration of CXCR5-positive cells as well as CXCL13/CD11b double-positive immune cells into the kidney, which affects CXCL13 expression and lupus-like nephritis.