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Article Abstract
Introduction: Sepsis is a life-threatening condition with a high mortality rate, yet its underlying mechanisms remain incompletely understood.
Objectives: This study investigates the role of the cleaved extracellular domain of signal regulatory protein alpha (SIRPα-ex) in the pathogenesis of sepsis.
Methods: The presence of shed SIRPα-ex was examined in the circulation of septic mice and patients. Functional assays involved neutralization of SIRPα-ex with an anti-SIRPα antibody and administration of recombinant SIRPα-ex-Fc in a murine sepsis model. Genetic models, including Sirpα and Sirpα-ct mice, were used to assess the contribution of SIRPα signaling.
Results: We found that Sirpα/ mice were protected from sepsis despite marked hyperinflammation, suggesting a cytokine-independent protective mechanism. Circulating SIRPα-ex was elevated in both septic mice and patients. Neutralization of SIRPα-ex significantly attenuated lipopolysaccharide (LPS)-induced sepsis, whereas administration of SIRPα-ex-Fc exacerbated disease severity. Mechanistically, SIRPα-ex was cleaved by the metalloproteinase ADAM10 and subsequently bound to erythrocyte CD47, triggering nitric oxide (NO) release. Inhibition of ADAM10 reduced plasma NO levels and vascular permeability in septic mice.
Conclusion: These findings identify shedding SIRPα-ex as a key exacerbating factor in sepsis via NO-mediated vascular dysfunction. Targeting SIRPα-ex shedding offers a potential therapeutic strategy for mitigating sepsis.
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| http://dx.doi.org/10.1016/j.jare.2025.08.019 | DOI Listing |
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