Background/Purpose: Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease characterized by dysregulation of both innate and adaptive immunity. Current therapeutic options are limited, and 20-40% of patients are unresponsive to treatment. C-X-C motif chemokine ligand 5 (CXCL5)

is known as a chemoattractant and activator of neutrophils. Our prior work identified CXCL5 as a key active factor secreted by mesenchymal stromal cells (MSCs) that was able to improve survival and reduce disease activity in a pre-clinical mouse model of graft versus host disease. However, whether CXCL5 could dampen inflammation and abrogate the pathological processes of SLE is unknown.

Methods: 16-week-old MLR/lpr (Fas^lpr) lupus-prone mice were treated with ten weekly intravenous doses of CXCL5 (3 µg/kg) and monitored for ten weeks. Immune and cytokine profiles were determined by flow cytometry and Luminex assays. Anti-DS DNA autoantibody levels were measured by ELISA. Proteinuria was evaluated by albumin creatinine ratio. Renal immune cell infiltration and complement 3 deposition were determined by Haematoxylin & Eosin and immunofluorescence staining. Potential molecular changes were identified by bulk RNA sequencing.

Results: Indeed, in MLR/lpr (Fas^lpr) lupus-prone mice, we found that intravenous treatment with CXCL5 significantly improved mouse survival with a concomitant reduction in anti-dsDNA levels, proteinuria, renal complement C3 deposition, leukocyte infiltration and neutrophil extracellular trap (NET) formation. Immune and molecular profiling and pharmacokinetic studies showed that CXCL5 treatment reduced inflammation via the orchestral suppression of effector cell (T_H17 cells, neutrophils and macrophages) proliferation mediated through T_H1 and T_H2 cells and leukocyte extravasation through restoration of the dysregulated CXCL5 blood-tissue chemokine gradient.

Conclusion: CXCL5 may represent a novel therapeutic option for SLE by restoring dysregulated innate and adaptive immune responses.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cxcl5-dampens-inflammation-in-murine-lupus-by-orchestral-suppression-of-effector-cell-proliferation-and-leukocyte-extravasation/