Immune regulation of hypoxia inducible factor alpha (HIF-1α) in the jawless vertebrate lamprey (Lethenteron camtschaticum)

Hypoxia-inducible factor 1α (HIF-1α) is a key transcription factor in cellular oxygen sensing and plays an important role in regulating innate immune responses. Although HIF-1α has been extensively studied in higher vertebrates, its function in primitive vertebrates remains unclear. In this study, we characterized and conducted functional analysis of HIF-1α (named Lc-HIF-1α) in the primitive jawless vertebrate lamprey (Lethenteron camtschaticum). The CDS length of Lc-HIF-1α is 2505 bp, encoding 834 amino acids. Although the sequence similarity to both human and zebrafish is only about 60%, the domains of Lc-HIF-1α are consistent with those of higher vertebrates and still exhibit similar immune responses and regulatory mechanisms. Lc-HIF-1α was significantly upregulated during multi-stimulation, and overexpression of Lc-HIF-1α significantly reduced the survival number of Escherichia coli in cells. Furthermore, Lc-HIF-1α promoted the production of reactive oxygen species (ROS) and upregulated the expression of pro-inflammatory factors, revealing the evolutionary conservation of the immune functions of HIF-1α. Notably, overexpression of Lc-HIF-1α slightly reduced phagocytosis and upregulated the expression of the anti-inflammatory factor TGF-β. These results suggest that Lc-HIF-1α may help preferentially clear intracellular pathogens through oxidative stress, while also using negative feedback to balance the inflammatory response. This study advances the understanding of the important role that HIF-1α plays in the immune response of the lamprey and deepens our knowledge of the immune mechanisms in primitive vertebrates.