Abstract
Cytokine storm syndrome (CSS) is associated with severe damage and high mortality in acute diseases. Over-activation of M1 macrophages, accompanied with excessive pro-inflammatory cytokine secretion, drives cytokine storms, while promoting M2 macrophage polarization is a potential CSS treatment. The liver, an immune-responsive organ, secretes hepatokines such as fibroblast growth factor-21 (FGF-21) to regulate macrophage activation, but knowledge of their role in CSS-related inflammation is elusive, fueling the search for new hepatokines that can effectively fine-tune the pro-inflammatory activation of macrophages during CSS. In this study, lipopolysaccharide (LPS)-induced CSS signals increase hepatic Angiopoietin-like protein 8 (Angptl8) expression. Angptl8 knockout (Angptl8-/-) reduces mortality in high-dose LPS-treated mice. This is due to inhibited M1 and enhanced M2 macrophage polarization, decreased pro-inflammatory cytokines, and alleviated CSS symptoms. Angptl8 promotes M1 polarization by activating glycogen metabolism via c-Jun N-terminal kinase (JNK) phosphorylation. Mice treated with an Angptl8-neutralizing antibody have improved CSS symptoms, and the antibody is non-toxic in vivo. Hence, Angptl8 is a promising CSS therapeutic target. Given cytokine storms' role in viral infections and immune therapy-related adverse reactions, targeting Angptl8 may provide new treatments, potentially improving patient outcomes and reducing morbidity and mortality.