Background/Purpose: Systemic lupus erythematous (SLE) is an autoimmune disease characterized by symptomatic flares that often result in terminal organ failure.   The pathogenesis is characterized by complex immune dysfunction, including aberrant T-cell responses.   FTY720, an FDA approved therapy for multiple sclerosis (MS), is a compound with the ability to modulate T-cell proliferation through S1P receptors.  The aim of this study is to attenuate tissue injury and define a subset of S1P receptors and expression patterns that may be altered in the autoimmune prone ischemic reperfusion injury (IRI) mouse model.

Methods: Immune competent (C57BL/6) and autoimmune prone (B6.MRL/lpr) mice were exposed to FTY720 or Pertussis toxin followed by superior mesenteric artery ischemic reperfusion injury.  Histological analysis of tissue samples was performed to assess tissue injury and the extent of inflammatory cell infiltration into the injured tissues.  Multiplex array based cytokine analysis and immunohistochemistry analysis of isolated tissue lysates established and confirmed the extent of induction of inflammatory cytokine production.  Immunofluorescence staining of tissue samples defined specific S1P receptor expression patterns.

Results: Targeting S1P receptors with FTY720 attenuates tissue injury in the autoimmune prone mice (B6.MRL/lpr) compared to the immune competent controls (C57BL/6).   Multi-ligand targeting the S1P receptors decreased T-cell infiltration, IL-6 and IL1B levels in the autoimmune prone mice compared to the immune competent controls.  Immunofluorescence staining of specific S1P receptors showed increased S1P1, S1P2 and S1P3 expression patterns in the autoimmune prone mice compared to the immune competent controls after ischemic reperfusion injury.

Conclusion: These findings support the hypothesis that S1P receptor interaction is a key regulator of T-cell mediated tissue injury and represents a novel therapeutic target in SLE.  The role of specific S1P receptors in the pathophysiology of tissue injury is highlighted by the increased expression patterns of targeted S1P receptors after ischemic reperfusion injury in autoimmune prone mice.   Defining S1P receptor expression in human lupus and how this expression influences the cell responsiveness during states of inflammation warrants further investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exploration-of-a-novel-therapeutic-target-in-a-murine-model-of-systemic-lupus-erythematosus-targeting-sphingosine-1-phosphate-s1p-receptors/