Loss of CMAH during Human Evolution Primed the Monocyte-Macrophage Lineage toward a More Inflammatory and Phagocytic State.
Humans and chimpanzees are more sensitive to endotoxin than are mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses inCmah-/-mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMP-N-acetylneuraminic acid hydroxylase (CMAH) loss occurred ∼2-3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the genusHomoCmah-/-mice manifested a decreased survival in endotoxemia following bacterial LPS injection. Macrophages fromCmah-/-mice secreted more inflammatory cytokines with LPS stimulation and showed more phagocytic activity. Macrophages and whole blood fromCmah-/-mice also killed bacteria more effectively. Metabolic reintroduction of Neu5Gc intoCmah-/-macrophages suppressed these differences.Cmah-/-mice also showed enhanced bacterial clearance during sublethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killedEscherichia coliand ingestedE. coliBioParticles better. Metabolic reintroduction of Neu5Gc into human macrophages suppressed these differences. Although multiple mechanisms are likely involved, one cause is altered expression of C/EBPβ, a transcription factor affecting macrophage function. Loss of Neu5Gc inHomolikely had complex effects on immunity, providing greater capabilities to clear sublethal bacterial challenges, possibly at the cost of endotoxic shock risk. This trade-off may have provided a selective advantage whenHomotransitioned to butchery using stone tools. The findings may also explain why theCmah-/-state alters severity in mouse models of human disease.
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
Jonathan J
0000-0002-3705-9060
JJ
Okerblom
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
Flavio
F
Schwarz
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
Josh
J
Olson
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Initiative for Maximizing Student Development Program, University of California, San Diego, La Jolla, CA 92093.
William
W
Fletes
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
Syed Raza
SR
Ali
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 42305.|Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH 43210; and.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205.
Paul T
PT
Martin
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
Christopher K
0000-0003-4344-3592
CK
Glass
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.|Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
Victor
V
Nizet
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; a1varki@ucsd.edu.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
Ajit
0000-0002-2206-975X
A
Varki
D000818:Animals; D001433:Bacteriolysis / Q000235:genetics; D005075:Biological Evolution; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D019446:Endotoxemia / Q000276:immunology*; D004926:Escherichia coli / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D002679:Pan troglodytes; D010587:Phagocytosis / Q000235:genetics
D008070:Lipopolysaccharides; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase