Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors

Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation due to a lack of mechanistic understanding. Specifically, CXCL4 (Platelet Factor 4, PF4) has no established receptor that explains its function. Here, we use biophysical, in vitro, and in vivo techniques to determine the mechanism underlying CXCL4-mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars on proteoglycans within the endothelial extracellular matrix, resulting in increased adhesion of leukocytes to the vasculature, increased vascular permeability, and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulfation confers selectivity onto chemokine localization. These findings present mechanistic insights into chemokine biology and provide future therapeutic targets

Metropolitan and city-regional politics in the urban age: why does “(smart) devolution” matter?

In recent years, two apparently contradictory but, in fact, complementary socio-political phenomena have reinforced each other in the European urban realm: the rescaling of nation-states through “devolution” and the emergence of two opposed versions of “nationalism” (that is, ethnic, non-metropolitanised, state-centric, exclusive, and right-wing populist nationalism and civic, metropolitanized, stateless, inclusive and progressivistemancipatory-social democratic nationalism). In light of these intertwined phenomena, this article shows how an ongoing, pervasive and uneven “metropolitanisation effect” is increasingly shaping city-regional political responses by overlapping metropolitan, cityregional, and national political scales and agendas. This effect is clear in three European cases driven by “civic nationalism” that are altering their referential nation-states’ uniformity through “devolution”. This article compares three metropolitan (and city-regional) cases in the United Kingdom and in Spain, namely, Glasgow (Scotland), Barcelona (Catalonia) and Bilbao (Basque Country), by benchmarking their policy implementation and the tensions produced in reference to their nation-states. Fieldwork was conducted from January 2015 to June 2017 through in-depth interviews with stakeholders in the three locations. Despite the so-called pluri-national and federal dilemmas, this article contributes to the examination of the side effects of “metropolitanisation” by considering three arguments based on geoeconomics (“prosperous competitiveness”), geo-politics (“smart devolution”), and geodemocratics (“right to decide”). Finally, this article adds to the existing research on metropolitan and city-regional politics by demonstrating why “devolution” matters and why it must be considered seriously. The “metropolitanisation effect” is key to understanding and transforming the current configurations of nation-states, such as the United Kingdom and Spain (as we currently know them), beyond internal discord around pluri-nationality and quasi-federalism. This article concludes by suggesting the term “smart devolution” to promote more imaginative and entrepreneurial approaches to metropolitan and city-regional politics, policies, and experimental democracy within these nation-states. These approaches can identify and pursue “smart” avenues of timely, subtle and innovative political strategies for change in the ongoing re-scaling devolution processes occurring in the United Kingdom and in Spain and in the consequent changes in the prospects for the refoundational momentum in the EU