Loss of CMAH During Human Evolution Primed the Monocyte-Macrophage Lineage Towards a More Inflammatory and Phagocytic State.

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Okerblom, JJ; Schwarz, F; Olson, J; Fletes, W; Ali, SR; Martin, PT; Glass, CK; Nizet, V; Ajit Varki
Year of Publication: 2017
Journal: Journal of Immunology
Volume: 198
Issue: 6
Pagination: 2366-2373
Date Published: 03/2017
Publication Language: eng
Abstract:

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 reintroduction 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 For Peer Review. Do not distribute. Destroy after use. to butchery using stone tools. The findings may also explain why the Cmah-/- state alters severity in mouse models of human disease. 

DOI: https://doi.org/10.4049/jimmunol.1601471
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