Humans and chimpanzees are more sensitive to endotoxin than mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses in Cmah−/− mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMAH loss occurred ~2-3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the genus Homo. Cmah−/− mice manifested a decreased survival in endotoxemia following bacterial lipopolysaccharide (LPS) injection. Macrophages from Cmah−/− mice secreted more inflammatory cytokines with LPS-stimulation and showed more phagocytic activity. Macrophages and whole blood from Cmah−/− mice also killed bacteria more effectively. Metabolic re-introduction of Neu5Gc into Cmah−/− macrophages suppressed these differences. Cmah−/− mice also showed enhanced bacterial clearance during sub-lethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed E. coli and ingested E. coli bioparticles better. Metabolic re-introduction of Neu5Gc into human macrophages suppressed these differences. While multiple mechanisms are likely involved, one cause is altered expression of C/EBPβ, a transcription factor affecting macrophage function. Loss of Neu5Gc in Homo likely had complex effects on immunity, providing greater capabilities to clear sub-lethal bacterial challenges, possibly at the cost of endotoxic shock risk. This trade-off may have provided a selective advantage when Homo transitioned to butchery using stone tools. The findings may also explain why the Cmah−/− state alters severity in mouse models of human disease.

BackgroundHypoxia inducible factor-1 (HIF-1) is a major regulator of the cellular adaption to low oxygen stress and the innate immune function of myeloid cells. Treatment with the novel HIF-1 stabilizing drug AKB-4924 has been shown to enhance the bactericidal activity of keratinocytes as well as phagocytic cells. In this study, we sought to investigate the effect of pharmacological boosting of HIF-1 with AKB-4924 in keratinocytes and their contribution to the innate immune response.FindingsTreatment with the novel HIF-1 stabilizing drug AKB-4924 can increase keratinocyte production of pro-inflammatory cytokines in vitro and enhance neutrophil recruitment in vivo.ConclusionsHIF plays an important role in cytokine production by keratinocytes and in neutrophil recruitment to the skin. The HIF-boosting drug AKB-4924 has the potential to enhance the immune response even in the complex environment of bacterial skin infections.

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