Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways.

OBJECTIVE: To determine the efficacy of CXCL5 administration in lupus-prone MRL/lpr (Faslpr ) mice and elucidate its working mechanisms. METHODS: CXCL5 expression in blood (obtained from SLE patients and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real-time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. RESULTS: In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti-double-stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short-term (10 weeks) and long-term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5-mediated immunomodulation occurred by promoting energy production in renal-infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. CONCLUSION: We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.

Maternal and Fetal Outcomes in Systemic Lupus Erythematosus Pregnancies.

INTRODUCTION: To describe the maternal and fetal outcomes in systemic lupus erythematosus (SLE) pregnancies followed-up in a single tertiary referral centre. METHODS: We performed a retrospective cohort study of 75 SLE pregnancies who were followed up in Singapore General Hospital over a 16-year period from 2000 to 2016. Adverse fetal and maternal outcomes including preterm delivery, miscarriages, fetal growth restriction, congenital heart block, neonatal lupus, pre-eclampsia and SLE flares were obtained from the medical records. RESULTS: The mean age at conception was 32 years old (SD 3.8). The mean SLE disease duration was 5.9 years (SD 5.2). The majority (88%) had quiescent SLE disease activity at baseline. Most pregnancies resulted in a live birth (74.7%). The mean gestational age at birth was 37.4 weeks (SD 3.4). Adverse fetal outcomes occurred in 53.3%. Preterm delivery (33.9%), miscarriages (20%) and fetal growth restriction (17.3%) were the most frequent adverse fetal outcomes. There was 1 neonatal death and SLE flares occurred in a third (33%). In the subgroup of SLE pregnancies with antiphospholipid syndrome, there were higher SLE flare rates (40%) and adverse fetal outcomes occurred in 8 pregnancies (80%). There were no predictive factors identified for all adverse fetal and maternal outcomes. In the subgroup analysis of preterm delivery, anti-Ro (SS-A) antibody positivity and hydroxychloroquine treatment were associated with a lower risk of preterm delivery. CONCLUSION: Although the majority had quiescent SLE disease activity at baseline, SLE pregnancies were associated with high rates of adverse fetal and maternal outcomes.