CD5L as a promising biological therapeutic for treating sepsis
Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here we demonstrate the utility of CD5 antigen-like (CD5L), a soluble protein also known as apoptosis inhibitor expressed by macrophages (AIM), for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that the protein's important and distinctive features include its ability to enhance neutrophil recruitment and activation, by increasing circulating levels of neutrophil chemoattractant CXCL1, and its capacity to promote neutrophil phagocytosis. We found that CD5L-deficient mice exhibited impaired neutrophil recruitment, and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibited a heightened pro-inflammatory transcriptional profile, reflecting loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorated measures of disease in the setting of high-grade CLP-induced sepsis, including a reduction in bacterial load, diminished inflammation, and improved mouse survival. Furthermore, rCD5L lowered endotoxin levels, mitigated the effects of damage-associated molecular patterns (DAMPs), and protected WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.