Immune tolerance-like pathway inhibits repair following white matter injury

White matter injury is associated with neurological dysfunction in a variety of conditions, ranging from cerebral palsy to vascular dementia. Oligodendrocyte progenitor cells (OPCs) are able to regenerate themselves and initiate a repair response following injury; however, the release of hyaluronic acid from the ECM following white matter injury impairs OPC maturation and remyelination. In this episode, Stephen Back and colleagues identify a bioactive hyaluronan fragment (bHAf) that selectively blocks OPC differentiation via activation of a noncanonical TLR4/AKT/FoxO3 signaling pathway. These results elucidate a mechanism by which white matter injury prevents repair and suggest that strategies to overcome this block in OPC maturation have potential for promoting regeneration after injury.

Vaginal epithelial shedding mediates ascending group B streptococcus infection

Group B streptococcus (GBS) is part of the normal vaginal flora of approximately 25% of healthy women. Unfortunately, GBS is associated with adverse pregnancy outcomes, due to in utero infection, and can cause serious infections in newborns, including pneumonia, sepsis, and meningitis. In this episode, Lakshmi Rajagopal and colleagues demonstrate that GBS promotes shedding of the vaginal epithelium, which in turn increases bacterial dissemination and ascending GBS infection. Importantly, prevention of epithelial exfoliation in murine models reduced ascending GBS infection and improved pregnancy outcomes.

A role for plasminogen activator inhibitor type 1 in skin fibrosis

Fibrosis is a characterized by excessive extracellular matrix deposition, resulting in tissue damage and loss of function. Activated fibroblasts are responsible for fibrotic phenotypes; however, the drivers of fibrosis are not fully understood. In this episode, Colin Jamora and Neha Pincha discuss their work, which shows that upregulation of plasminogen activator inhibitor type 1 (PAI1) on keratinocytes in mice with scleroderma-like disease promotes mast cell infiltration into the skin, subsequently increasing fibroblast activation and exacerbating fibrosis. The results of this study suggest that PAI1 should be further explored as a target for limiting fibrosis.

CD163+ macrophages serve pathogenic role in atherosclerosis

Macrophage polarization in response to stimuli within the microenvironment results in heterogeneous populations that can differentially influence disease. Atherosclerosis is largely inflammatory, with lipids driving polarization of M1 macrophages; however, alternatively activated, hemoglobin-scavenging CD163⁺ macrophages are present within atherosclerotic lesions and have been proposed to serve an antiinflammatory role. In this episode, Aloke Finn and Liang Guo discuss their work, which shows that CD163⁺ macrophages actually promote angiogenesis, vessel permeability, and leucocyte infiltration, thereby exacerbating plaque progression. The pathogenic effects of this alternatively activated population were driven by HIF1α/VEGF-A signaling, suggesting this pathway as a potential therapeutic target.

Tie1 deficiency limits cancer progression and metastasis

As primary tumor progression to metastasis dramatically increases mortality in patients with cancer, strategies to limit tumor cell growth and spread are of great interest. The orphan receptor tyrosine kinase Tie1 is highly expressed in intratumoral vasculature; however, the contribution of this receptor to tumor progression has not been defined. In this episode, Hellmut Augustin and Silvia La Porta, aided by original artwork by Carleen Spegg, discuss their work, which shows that loss of Tie1 in endothelial cells reduces primary tumor progression and limits metastasis. The results of this study indicate that Tie1 should be further explored as a therapeutic target for limiting cancer progression.