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CXCL5 administration dampens inflammation and improves survival 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 (SLE patients and Faslpr mice) and major internal organs (Faslpr mice) was examined by Luminex, real-time PCR and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Institute of Cancer Research (ICR) healthy and Faslpr mice. The efficacy of CXCL5 administration was demonstrated in Faslpr mice. Working mechanism was elucidated by flow cytometry, Luminex and RNA sequencing.


RESULTS
In SLE patients, serum CXCL5 levels were significantly lower than healthy individuals and negatively correlated with disease activity (p < 0.0001). 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-dsDNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements and neutrophil extracellular traps over 10 weeks and 2 years. In vitro and in vivo assays demonstrated CXCL5 dictated neutrophil trafficking, 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, reducing tissue fibrosis, granulocyte extravasation, complement components, interferons, and activating certain T cells. Further factorial design results indicate that CXCL5 appears to enhance host tolerability to cyclophosphamide in those vulnerable individuals.


CONCLUSION
Taken together, CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.