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Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in
Experimental Lung Injury by Enhanced Expression of CXCL12
#MMPMID28179498
Tan J
; Tedrow JR
; Nouraie M
; Dutta JA
; Miller DT
; Li X
; Yu S
; Chu Y
; Juan-Guardela B
; Kaminski N
; Ramani K
; Biswas PS
; Zhang Y
; Kass DJ
J Immunol
2017[Mar]; 198
(6
): 2269-2285
PMID28179498
show ga
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the
accumulation of apoptosis-resistant fibroblasts in the lung. We have previously
shown that high expression of the transcription factor Twist1 may explain this
prosurvival phenotype in vitro. However, this observation has never been tested
in vivo. We found that loss of Twist1 in COL1A2(+) cells led to increased
fibrosis characterized by very significant accumulation of T cells and bone
marrow-derived matrix-producing cells. We found that Twist1-null cells expressed
high levels of the T cell chemoattractant CXCL12. In vitro, we found that the
loss of Twist1 in IPF lung fibroblasts increased expression of CXCL12 downstream
of increased expression of the noncanonical NF-?B transcription factor RelB.
Finally, blockade of CXCL12 with AMD3100 attenuated the exaggerated fibrosis
observed in Twist1-null mice. Transcriptomic analysis of 134 IPF patients
revealed that low expression of Twist1 was characterized by enrichment of T cell
pathways. In conclusion, loss of Twist1 in collagen-producing cells led to
increased bleomycin-induced pulmonary fibrosis, which is mediated by increased
expression of CXCL12. Twist1 expression is associated with dysregulation of T
cells in IPF patients. Twist1 may shape the IPF phenotype and regulate
inflammation in fibrotic lung injury.
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