title: WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury.
abstract: We recently noted that the matricellular protein WISP1 contributes to sepsis induced acute lung injury (ALI) via integrin β6. In the current study, we pursued further aspects of WISP1 modulation of TLR signaling in lungs of mice after sepsis and TLR4 mediated release of TNF-α in macrophages. After confirming that TLR4 and CD14 are critical in transducing sepsis mediated ALI, we now demonstrate that intrapulmonary αvβ3 is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion. Comparison of cultured macrophages revealed that WISP1 increased release of TNF-α from RAW264.7 cells with baseline expression of αvβ3, but primary cultures of peritoneal macrophages (PMø) required activation of TLR4 to induce de novo synthesis of αvβ3 enabling WISP1 to stimulate release of TNF-α. The specific requirement for β3 integrin was apparent when the effect of WISP1 was lost in PMø isolated from β3(-/-) mice. WISP1 enhanced TLR4 mediated ERK signaling and U0126 (an ERK inhibitor) blocked LPS induced β3 integrin expression and WISP1 enhanced TNF-α release. Collectively these data suggest that WISP1-αvβ3 integrin signaling is involved in TLR4 pathways in macrophages and may be an important contributor to TLR4/CD14 mediated inflammation in sepsis induced lung injury.
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University school of Medicine, Shanghai, China.|Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University school of Medicine, Shanghai, China.
authors.forename: Xibing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University school of Medicine, Shanghai, China.
authors.forename: Shuqing
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pitt
authors.affiliation: Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Billiar
authors.affiliation: Department of Anesthesiology, East Hospital, Tongji University school of Medicine, Shanghai, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000494:pharmacology; D002478:Cells, Cultured; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D039302:Integrin alphaVbeta3; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha