ADAM8 signaling drives neutrophil migration and ARDS severity

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain

The role of matrix- and disintegrin-metalloproteinases in neurodegenerative diseases

Schlomann U. The role of matrix- and disintegrin-metalloproteinases in neurodegenerative diseases. Bielefeld; 2002

The stimulation of dendrite growth by Sema3A requires integrin engagement and focal adhesion kinase.

The rate and direction of axon and dendrite growth depend on multiple guidance signals and growth factors. Semaphorin 3A (Sema3A) acts as a repellent for axons and attractant for dendrites. Here, we show that the requirement for integrin engagement distinguishes the response of axons and dendrites to Sema3A in hippocampal neurons. Sema3A promotes the extension of hippocampal dendrites by a pathway that requires focal adhesion kinase (FAK). The stimulation of dendrite growth and FAK phosphorylation by Sema3A depend on integrin engagement. Unlike their function as a target of Sema3A during the collapse of axonal growth cones, integrins facilitate the stimulation of dendrite extension. Conditional inactivation of the genes encoding beta1 integrin or FAK blocks the growth-promoting effect of Sema3A but not the collapse of axonal growth cones. Our results demonstrate that different pathways mediate the stimulation of dendrite growth and the collapse of axonal growth cones by Sema3A

ADAM8/MS2/CD156, an Emerging Drug Target in the Treatment of Inflammatory and Invasive Pathologies

While it is highly accepted that ADAM family members with ubiquitous expression patterns, such as ADAM10 and ADAM17 have major roles in homoeostasis and pathology, ADAM8 was initially considered as an immune-specific ADAM with a cell-specific expression pattern. Therefore, ADAM8 had a “sleeping beauty” existence for many years, and has recently come back into focus as it was detected under several pathological conditions. These were found to typically involve inflammation and remodelling of the extracellular matrix, including cancers and serious respiratory diseases such as asthma. In these diseases, induced expression of ADAM8 by different stimuli results in cleavage of various substrates, including cell adhesion molecules, cytokine receptors, and ECM components. Involvement of ADAM8 in individual diseases indicates its usefulness as both a diagnostic and prognostic marker. Even more strikingly, as ADAM8 progressively emerges as a key effector in pathological processes, so does its attractiveness as a therapeutic target rather than being a mere indicator of disease and its progression. This is encouraged by analysis of ADAM8 null mice, identifying no adverse phenotype in the absence of functional ADAM8. Thus, ADAM8 potentially is an attractive drug target in a variety of diseases. In this review, the current knowledge on ADAM8 in diseases and avenues for specific inhibition based on unique biochemical features of ADAM8 will be presented

Altered Heparan Sulfate Structure in Mice with Deleted NDST3 Gene Function*S⃞

We report the generation and analysis of mutant mice bearing a targeted disruption of the heparan sulfate (HS)-modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 3 (NDST3). NDST3-/- mice develop normally, are fertile, and show only subtle hematological and behavioral abnormalities in agreement with only moderate HS undersulfation. Compound mutant mice made deficient in NDST2;NDST3 activities also develop normally, showing that both isoforms are not essential for development. In contrast, NDST1-/-;NDST3-/- compound mutant embryos display developmental defects caused by severe HS undersulfation, demonstrating NDST3 contribution to HS synthesis in the absence of NDST1. Moreover, analysis of HS composition in dissected NDST3 mutant adult brain revealed regional changes in HS sulfation, indicating restricted NDST3 activity on nascent HS in defined wild-type tissues. Taken together, we show that NDST3 function is not essential for development or adult homeostasis despite contributing to HS synthesis in a region-specific manner and that the loss of NDST3 function is compensated for by the other NDST isoforms to a varying degree