The Journal of pathology
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The Journal of pathology · Aug 2014
Triggering receptor expressed on myeloid cells-1 (TREM-1) improves host defence in pneumococcal pneumonia.
Streptococcus (S.) pneumoniae is a common Gram-positive pathogen in community-acquired pneumonia and sepsis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor on phagocytes known to amplify inflammatory responses. Previous studies showed that TREM-1 inhibition protects against lethality during experimental Gram-negative sepsis. ⋯ Trem-1/3(-/-) alveolar macrophages produced fewer cytokines upon exposure to S. pneumoniae in vitro and were less capable of phagocytosing this pathogen. TREM-1/3 deficiency did not influence neutrophil responsiveness to S. pneumoniae. These results identify TREM-1 as a key player in protective innate immunity during pneumococcal pneumonia, most likely by enhancing the early immune response of alveolar macrophages.
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The Journal of pathology · May 2014
Role of metallothioneins as danger signals in the pathogenesis of colitis.
Inflammatory bowel diseases (IBDs) are recurrent intestinal pathologies characterized by a compromised epithelial barrier and an exaggerated immune activation. Mediators of immune cell infiltration may represent new therapeutic opportunities. Metallothioneins (MTs) are stress-responsive proteins with immune-modulating functions. ⋯ In a Boyden chamber migration assay, leukocyte attraction towards the necrotic cell supernatant could be abolished with anti-MT antibody, indicating the chemotactic potential of endogenous released MT. Our results show that human colitis is associated with infiltration of MT-positive inflammatory cells. Since antibody blockade of extracellular MT can reduce colitis in mice, MT may act as a danger signal and may represent a novel target for reducing leukocyte infiltration and inflammation in IBD patients.
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The Journal of pathology · Mar 2014
The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. ⋯ Conversely, in the absence of αB-crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-β1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases.
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The Journal of pathology · Feb 2014
Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain.
Although the incidence of breast cancer metastasis (BCM) in brain has increased significantly in triple-negative breast cancer (TNBC), the mechanisms remain elusive. Using in vivo mouse models for BCM in brain, we observed that TNBC cells crossed the blood-brain barrier (BBB), lodged in the brain microvasculature and remained adjacent to brain microvascular endothelial cells (BMECs). Breaching of the BBB in vivo by TNBCs resulted in increased BBB permeability and changes in ZO-1 and claudin-5 tight junction (TJ) protein structures. ⋯ Secreted Ang-2 impaired TJ structures and increased BBB permeability. Treatment of mice with the neutralizing Ang-2 peptibody trebananib prevented changes in the BBB integrity and BMEC destabilization, resulting in inhibition of TNBC colonization in brain. Thus, Ang-2 is involved in initial steps of brain metastasis cascade, and inhibitors for Ang-2 may serve as potential therapeutics for brain metastasis.