Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-ß1 from ECM stores.

In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-ß1 from the extracellular matrix (ECM) stores. Liberation of active TGF-ß1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.

Specific high affinity interaction of Helicobacter pylori CagL with integrin αV ß6 promotes type IV secretion of CagA into human cells.

CagL is an essential pilus surface component of the virulence-associated type IV secretion system (T4SS) employed by Helicobacter pylori to translocate the oncogenic effector protein CagA into human gastric epithelial cells. CagL contains an RGD motif and integrin α5 ß1 is widely accepted as its host cell receptor. Here, we show that CagL binds integrin αV ß6 with substantially higher affinity and that this interaction is functionally important. Cell surface expression of αV ß6 on various cell lines correlated perfectly with cell adhesion to immobilized CagL and with binding of soluble CagL to cells. We found no such correlation for α5 ß1 . The purified αV ß6 ectodomain bound CagL with high affinity. This interaction was highly specific, as the affinity of CagL for other RGD-binding integrins was two to three orders of magnitude weaker. Mutation of either conserved leucine in the CagL RGDLXXL motif, a motif that generally confers specificity for integrin αV ß6 and αV ß8 , lowered the affinity of CagL for αV ß6 . Stable expression of αV ß6 in αV ß6 -negative but α5 ß1 -expressing human cells promoted two hallmarks of the functional H. pylori T4SS, namely translocation of CagA into host cells and induction of interleukin-8 secretion by host cells. These findings suggest that integrin αV ß6 , although not essential for T4SS function, represents an important host cell receptor for CagL.

LRP1: A chameleon receptor of lung inflammation and repair.

The lung displays a remarkable capability to regenerate following injury. Considerable effort has been made thus far to understand the cardinal processes underpinning inflammation and reconstruction of lung tissue. However, the factors determining the resolution or persistence of inflammation and efficient wound healing or aberrant remodeling remain largely unknown. Low density lipoprotein receptor-related protein 1 (LRP1) is an endocytic/signaling cell surface receptor which controls cellular and molecular mechanisms driving the physiological and pathological inflammatory reactions and tissue remodeling in several organs. In this review, we will discuss the impact of LRP1 on the consecutive steps of the inflammatory response and its role in the balanced tissue repair and aberrant remodeling in the lung.