Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Drug
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Compound
Target Concepts:
Gene/Protein
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Query: UMLS:C0034069 (
pulmonary fibrosis
)
7,050
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with
pulmonary fibrosis
; however, the mechanism has not been fully defined. Gab1 and
Gab2
proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and
Gab2
were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs.
In vitro
Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore,
in vivo
conditional removal of
Gab1
(Gab1
MyKO
) and germ line knock-out of
Gab2
(
Gab2
-/-
) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of
Gab2
suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven
pulmonary fibrosis
in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.
...
PMID:Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice. 2868 32
