Figure 7. Hypothesis schema.

eCIRP promotes macrophage endotoxin tolerance. eCIRP is increased during sepsis or other disease conditions and recognizes its novel receptor, IL-6R, expressed in macrophages. This leads to the activation of downstream transcription factor STAT3, which results in immune tolerance as depicted by decreased levels of TNF-α and IL-6 following LPS stimulation to these macrophages. eCIRP treatment of macrophages also induces regulatory phenotype M2 polarization in macrophages through IL-6R–dependent STAT3 activation. Inhibition of IL-6R by using its neutralizing Ab decreases eCIRP-induced STAT3 activation in macrophages and corrects immune tolerance and M2 polarization.