Angiopoietin-like protein 8 orchestrates macrophage glycogen metabolism and polarization via the JNK signaling pathway in cytokine storm syndrome

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.