Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages.
gp96 is an endoplasmic reticulum chaperone for cell-surface Toll-like receptors (TLRs). Little is known about its roles in chaperoning other TLRs or in the biology of macrophage in vivo. We generated a macrophage-specific gp96-deficient mouse. Despite normal development and activation by interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta, the mutant macrophages failed to respond to ligands of both cell-surface and intracellular TLRs including TLR2, TLR4, TLR5, TLR7, and TLR9. Furthermore, we found that TLR4 and TLR9 preferentially interacted with a super-glycosylated gp96 species. The categorical loss of TLRs in gp96-deficient macrophages operationally created a conditional and cell-specific TLR null mouse. These mice were resistant to endotoxin shock but were highly susceptible to Listeria monocytogenes. Our results demonstrate that gp96 is the master chaperone for TLRs and that macrophages, but not other myeloid cells, are the dominant source of proinflammatory cytokines during endotoxemia and Listeria infections.
Yang
Yi
Y
Department of Immunology, MC 1601, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
Liu
Bei
B
Dai
Jie
J
Srivastava
Pramod K
PK
Zammit
David J
DJ
Lefrançois
Leo
L
Li
Zihai
Z
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D047468:Immunoprecipitation; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051193:Toll-Like Receptors; C053387:endoplasmin