Emerging evidence suggests that the TH17 subset of αβ T cells contributes to the development of allergic asthma. In this study we found that mice lacking αvβ8 on dendritic cells failed to generate TH17 cells in the lung and were protected from AHR in response to house dust mite and ovalbumin sensitization and challenge. Because loss of TH17 cells inhibited airway narrowing without obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of TH17 cytokines on mouse and human airway smooth muscle function. IL-17A enhanced contractile force generation through a NF-κB/RhoA/ROCK2 signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after OVA sensitization and challenge, and the diminished contraction of tracheal rings from these mice was reversed by IL-17A. These data indicate that IL-17A produced by TH17 cells contributes to allergen-induced AHR through direct effects on airway smooth muscle.

The integrin receptor ␣v␤5 controls two independent forms of interactions of the retinal pigment epithelium (RPE) with adjacent photoreceptor outer segments that are essential for vision. ␣v␤5 localizes specifically to apical microvilli of the RPE and contributes to retinal adhesion that maintains RPE contacts with intact outer segments at all times. Additionally, ␣v␤5 synchronizes diurnal bursts of RPE phagocytosis that clear photoreceptor outer segment fragments (POS) shed in a circadian rhythm. Dependence of retinal phagocytosis and adhesion on ␣v␤5 receptors suggests that the extracellular matrix ensheathing RPE microvilli contains ligands for this integrin. Here we studied mice lacking expression of functional MFG-E8 to test the contribution of this integrin ligand to ␣v␤5 functions in the retina. Lack of MFG-E8 only minimally reduced retinal adhesion. In contrast, lack of MFG-E8, like lack of ␣v␤5 receptor, eliminated ␣v␤5 downstream signaling involving the engulfment receptor MerTK and peak POS phagocytosis, both of which follow light onset in wild-type retina. MFG-E8-deficient RPE in primary culture retained normal epithelial morphology and levels of apical ␣v␤5 receptors, but showed impaired binding and engulfment of isolated POS. Soluble or POS-bound recombinant MFG-E8 was sufficient to fully restore phagocytosis by MFG-E8-deficient RPE. Furthermore, MFG-E8 supplementation strongly increased POS binding by wild-type and MerTK-deficient RPE, but did not affect POS binding by RPE lacking ␣v␤5. Thus, MFG-E8 stimulates rhythmic POS phagocytosis by ligating apical ␣v␤5 receptors of the RPE. These results identify MFG-E8 as the first extracellular ligand in the retina that is essential for diurnal POS phagocytosis.adhesion ͉ photoreceptors ͉ retinal pigment epithelium ͉ circadian rhythm ͉ outer segment T he phototransduction machinery of retinal rod and cone photoreceptor neurons localizes to their outer segment portions, which face the apical surface of the retinal pigment epithelium (RPE). Interactions of RPE cells with outer segments support photoreceptor function. RPE cells employ apical surface receptors at all times to promote retinal adhesion stabilizing alignment and RPE microvilli interdigitation with outer segments. Once a day, RPE cells use their apical phagocytic receptors and engulfment machinery to respond to circadian shedding of photoreceptor outer segment fragments (POS) with a vigorous burst of POS phagocytosis. Disruption of retinal adhesion in persistent retinal detachment or incomplete POS clearance by the RPE cause outer segment degeneration and photoreceptor apoptosis (1). Thus, intact receptor-mediated interactions of RPE cells with POS are critical to maintaining vision for life.␣v␤5 integrin is the only integrin family receptor at the apical surface of the RPE in rodent and human retina (2, 3). ␤5 integrin knockout (␤5 Ϫ/Ϫ ) mice show greatly weakened retinal adhesion at all times of day (4). Furthermore, ␤5 Ϫ/Ϫ retina lacks the daily rhythm of RPE phagocytosis because ␤5 Ϫ/Ϫ RPE fa...

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8 -/-mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8 +/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8 -/-macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.

Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.

Highlights d Beige fat progenitors are marked by cell surface proteins, PDGFRa, Sca1, and CD81 d Beige APC proliferation is regulated by temperature, genetic background, and aging d CD81 mediates integrin-FAK signaling in response to irisin d CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation

Background:The growing body of data on tumor-associated macrophages largely neglects phagocytosis of apoptotic cells. Results: MFG-E8, induced during efferocytosis, contributes to macrophage polarization with STAT3/SOCS3 pathway involvement. Conclusion: Efferocytosis induces macrophage polarization into tumor-associated macrophages mediated by MFG-E8. Significance: A novel tumor-promoting mechanism for macrophage polarization through efferocytosis and MFG-E8 and its corresponding signaling pathway were identified.

Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8−/−) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin– and αvβ5 integrin–dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.