Latent-TGF-β has a domain swapped architecture.

The multifunctional cytokine TGF-b is produced in a latent form (L-TGF-b) where a RGD containing homodimeric prodomain forms a "ring" encircling mature TGF-b, shielding it from its receptors. Thus L-TGF-b must be activated to function, a process driven by dynamic allostery resulting from integrin binding the L-TGF-b RGD motif. Here we provide critical evidence that defines a domain-swapped architecture of L-TGF-b, an essential component in the dynamic allostery mechanism of L-TGF-b activation.

Measurement of Cell Intrinsic TGF-β Activation Mediated by the Integrin αvβ8.

Transforming growth factor beta (TGF-β) is a multi-functional cytokine that plays a significant role in multiple diseases, including fibrosis and tumor progression. Whilst the biologic effects of TGF-β are well characterized, it is unclear how TGF-β signaling is regulated to impart specific responses within certain cell types. One mechanism of regulation may be through TGF-β activation, since TGF-β is always expressed in a latent form (L-TGF-β).

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury.

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (Mac) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages.

Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria.

Alveolar formation requires coordinated movement and interaction between alveolar epithelial cells, mesenchymal myofibroblasts, and endothelial cells/pericytes to produce secondary septa. These processes rely on the acquisition of distinct cellular properties to enable ligand secretion for cell-cell signaling and initiate morphogenesis through cellular contraction, cell migration, and cell shape change. In this study, we showed that mitochondrial activity and distribution play a key role in bestowing cellular functions on both alveolar epithelial cells and mesenchymal myofibroblasts for generating secondary septa to form alveoli in mice.