Humanin Attenuates Inflammatory Liver Injury and NF-κB Activation During Systemic Hypervirulent Klebsiella pneumoniae Infection

Abstract

Hypervirulent Klebsiella pneumoniae (hvKP) causes invasive infections, including bloodstream infections and liver abscesses, and dysregulated host inflammation may exacerbate liver injury. We investigated whether pretreatment with Humanin, a mitochondria-derived anti-inflammatory peptide, could attenuate hvKP-associated liver injury. We measured serum Humanin in 20 patients with hvKP-associated bloodstream infection and liver abscess and 20 matched healthy controls. C57BL/6 mice received intraperitoneal Humanin (2.5 or 5 mg/kg/day) for five days before intravenous hvKP challenge. We assessed liver injury, inflammatory responses, hepatic transcriptomes, NF-κB activation, and survival. Serum Humanin was higher in patients than in the controls (p < 0.001). In infected mice, Humanin pretreatment was associated with less prominent histopathological liver injury and lower serum ALT, AST, and PCT, hepatic myeloperoxidase activity, F4/80 immunoreactivity, CD86 fluorescence, and pro-inflammatory gene expression. The effects were generally greater at 5 mg/kg than at 2.5 mg/kg. Transcriptomic analysis showed attenuation of inflammatory pathways, including NF-κB signaling (NES = −1.86, p = 0.002, FDR = 0.012). Humanin also reduced p-p65/p65 and p-IκBα/IκBα ratios in liver tissue and hvKP-stimulated bone-marrow-derived macrophages; 5 mg/kg prolonged survival (p < 0.05). Humanin pretreatment may therefore limit inflammatory liver injury during systemic hvKP infection. This effect was associated with reduced macrophage-associated inflammation and NF-κB activation, although its molecular targets remain unknown.