title: The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes.
abstract: Treatment with the TLR4 agonist MPLA augments innate resistance to common bacterial pathogens. However, the cellular and molecular mechanisms by which MPLA augments innate immunocyte functions are not well characterized. This study examined the importance of MyD88- and TRIF-dependent signaling for leukocyte mobilization, recruitment, and activation following administration of MPLA. MPLA potently induced MyD88- and TRIF-dependent signaling. A single injection of MPLA caused rapid mobilization and recruitment of neutrophils, a response that was largely mediated by the chemokines CXCL1 and -2 and the hemopoietic factor G-CSF. Rapid neutrophil recruitment and chemokine production were regulated by both pathways although the MyD88-dependent pathway showed some predominance. In further studies, multiple injections of MPLA potently induced mobilization and recruitment of neutrophils and monocytes. Neutrophil recruitment after multiple injections of MPLA was reliant on MyD88-dependent signaling, but effective monocyte recruitment required activation of both pathways. MPLA treatment induced expansion of myeloid progenitors in bone marrow and upregulation of CD11b and shedding of L-selectin by neutrophils, all of which were attenuated in MyD88- and TRIF-deficient mice. These results show that MPLA-induced neutrophil and monocyte recruitment, expansion of bone marrow progenitors and augmentation of neutrophil adhesion molecule expression are regulated by both the MyD88- and TRIF-dependent pathways.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; antonio.hernandez@vanderbilt.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Liming
authors.initials: L
authors.lastname: Luan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Chase
authors.initials: C
authors.lastname: McAdams
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Jingbin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D054360:Chemokine CXCL1 / Q000502:physiology; D054426:Chemokine CXCL2 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D007113:Immunity, Innate; D019041:L-Selectin / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D038042:Myelopoiesis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D039481:CD11b Antigen; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016179:Granulocyte Colony-Stimulating Factor; D019041:L-Selectin; D008050:Lipid A; D053594:Myeloid Differentiation Factor 88; D023063:Receptors, Interleukin-8B; D051197:Toll-Like Receptor 4; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C048436:monophosphoryl lipid A
keywords: TLR4; cytokines; innate immunity; monocyte; myeloid progenitors; neutrophil