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Li Z
; Scott MJ
; Fan EK
; Li Y
; Liu J
; Xiao G
; Li S
; Billiar TR
; Wilson MA
; Jiang Y
; Fan J
Cell Death Differ
2016[Sep]; 23
(9
): 1428-47
PMID26943325
show ga
Infection is a common clinical complication following tissue damage resulting
from surgery and severe trauma. Studies have suggested that cell pre-activation
by antecedent trauma/tissue damage profoundly impacts the response of innate
immune cells to a secondary infectious stimulus. Cell necroptosis, a form of
regulated inflammatory cell death, is one of the mechanisms that control cell
release of inflammatory mediators from important innate immune executive cells
such as macrophages (M?), which critically regulate the progress of inflammation.
In this study, we investigated the mechanism and role of trauma/tissue damage in
the regulation of LPS-induced M? necroptosis using a mouse model simulating
long-bone fracture. We demonstrate that LPS acting through Toll-like receptor
(TLR) 4 promotes M? necroptosis. However, necroptosis is ameliorated by
high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1
acting through cell surface receptor for advanced glycation end products (RAGE)
upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4
internalization and desensitization to decrease M? necroptosis. We further show
that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription
factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional
upregulation. These results reveal a previous unidentified protective role of
damage-associated molecular pattern (DAMP) molecules in restricting inflammation
in response to exogenous pathogen-associated molecular pattern molecules.
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