The IFN-inducible GTPase LRG47 (Irgm1) negatively regulates TLR4-triggered proinflammatory cytokine production and prevents endotoxemia.
LRG47/Irgm1, a 47-kDa IFN-inducible GTPase, plays a major role in regulating host resistance as well as the hemopoietic response to intracellular pathogens. LRG47 expression in macrophages has been shown previously to be stimulated in vitro by bacterial LPS, a TLR4 ligand. In this study, we demonstrate that induction of LRG47 by LPS is not dependent on MyD88 signaling, but rather, requires STAT-1 and IFN-beta. In addition, LRG47-deficient mice are highly susceptible to LPS, but not TLR2 ligand-induced shock, an outcome that correlates with enhanced proinflammatory cytokine production in vitro and in vivo. Further analysis revealed that LPS-stimulated LRG47-deficient macrophages display enhanced phosphorylation of p38, a downstream response associated with TLR4/MyD88 rather than IFN-beta/STAT-1 signaling. In contrast, LPS-induced phosphorylation of IFN regulatory factor-3 and expression of IFN-beta or the type I IFN-regulated genes, CCL5 and CCL10, were unaltered in LRG47(-/-) cells. Together, these observations indicate that in LPS-stimulated murine macrophages LRG47 is induced by IFN-beta and negatively regulates TLR4 signaling to prevent excess proinflammatory cytokine production and shock. Thus, our findings reveal a new host-protective function for this GTPase in the response to pathogenic encounter.
Bafica
Andre
A
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. abafica@niaid.nih.gov
Feng
Carl G
CG
Santiago
Helton C
HC
Aliberti
Julio
J
Cheever
Allen
A
Thomas
Karen E
KE
Taylor
Gregory A
GA
Vogel
Stefanie N
SN
Sher
Alan
A
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology*; D019446:Endotoxemia / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016899:Interferon-beta / Q000502:physiology; D007372:Interferons / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D019204:GTP-Binding Proteins; D018836:Inflammation Mediators; D016899:Interferon-beta; D007372:Interferons; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D051197:Toll-Like Receptor 4; C096000:Ifi1 protein, mouse; C494080:Stat1 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse