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.
Highlights
On endothelial cells in mediating increases in alveolar permeability in multiple models of acute lung injury[12]
Less is known about β3 and WISP1, we recently found that WISP1-integrinβ[3] interaction contributed to mechanical ventilation augmented PolyI:C induced lung injury14. αvβ[3] integrin is a ubiquitous receptor that is expressed on a wide variety of cell types including differentiated macrophage[15,16]
We sought to detect the effect of global genetic ablation of TLR4 or CD14 (TLR4−/−, CD14−/−) in a clinically relevant model of polymicrobial sepsis caused by cecal ligation and puncture (CLP) in mice
Summary
On endothelial cells in mediating increases in alveolar permeability in multiple models of acute lung injury[12]. Β3 integrin appeared important in endothelial cell barrier protection in intraperitoneal LPS and CLP17, other studies have indicated that αvβ[3] is linked to inflammation and could be a potential macrophage activator[18,19,20,21]. We noted that: a) intrapulmonary αvβ[3] is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion; b) β3 is required for WISP1 to enhance TLR4 mediated activation of TNF-αrelease from primary cultures of PMø; and c) ERK signaling is important in enhancing and transducing WISP1 synergetic effect
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