Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns.

Cell migration has two opposite faces: although necessary for physiological processes such as immune responses, it can also have detrimental effects by enabling metastatic cells to invade new organs. In vivo, migration occurs in complex environments and often requires a high cellular deformability, a property limited by the cell nucleus. Here we show that dendritic cells, the sentinels of the immune system, possess a mechanism to pass through micrometric constrictions. This mechanism is based on a rapid Arp2/3-dependent actin nucleation around the nucleus that disrupts the nuclear lamina, the main structure limiting nuclear deformability. The cells' requirement for Arp2/3 to pass through constrictions can be relieved when nuclear stiffness is decreased by suppressing lamin A/C expression. We propose a new role for Arp2/3 in three-dimensional cell migration, allowing fast-moving cells such as leukocytes to rapidly and efficiently migrate through narrow gaps, a process probably important for their function.

Leukocyte extravasation involves interdependent signaling pathways underlying the complex dynamics of firm adhesion, crawling, and diapedesis. While signal transduction by agonist-bound chemokine receptors plays a central role in the above responses, it is unclear how it contributes to the sustained and concurrent nature of such responses, given the rapid kinetics of chemokine-induced trimeric G protein coupling and homologous desensitization. Our findings unveil a novel role of ␤-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in ␤-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited ␤-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both ␤ 1 and ␤ 2 integrins. While both ␤-arrestin isoforms are required for rapid keratinocyte-derived chemokine (KC)-induced arrest onto limiting amounts of vascular cell adhesion molecule-1 (VCAM-1), adhesion strengthening under shear is selectively dependent on ␤-arrestin 2. The latter synergizes with phospholipase C in promoting activation of Rap1A and B, both of which cooperatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced G␣ i and ␤-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation. IntroductionLeukocyte extravasation in response to both homeostatic and inflammatory cues is a multistep process involving rapid integrinmediated arrest to the adluminal side of postcapillary venules, as a prerequisite for both transcellular and paracellular diapedesis across the vascular endothelium. 1-3 Capture of circulating leukocytes and subsequent rolling, primarily mediated by selectins, 4 precede and facilitate integrin-dependent firm adhesion, which is dynamically regulated by the interplay of chemokines and adhesion molecules. Circulating leukocytes maintain their integrins in a low-adhesive state that can undergo in situ up-regulation by chemokine-bound G␣ i protein-coupled receptors (GPCRs) via cytoplasmic changes ("inside-out" signaling). [5][6][7] Concurrently, binding of endothelial adhesion molecules stabilizes the active conformation of integrins by "outside-in" signaling, further contributing to the dynamics of leukocyte adhesion under flow. 8,9 Adhesion strengthening at the adluminal side of the endothelium in postcapillary venules allows firmly adherent leukocytes to resist hemodynamic shear forces in the order of 0.1 to 1 pN/m 2 . 10 Signaling cascades originating from chemokine-bound GPCRs orchestrate the complex dynamics of leukocyte adhesion, crawling, and directed migration, that concur in promoting the extravasation of leukocytes. 3,7 Several interdependent pathways invoked by chemokine receptor triggering have been shown to effect selected steps in this process. Intriguing...

The rise of neurodegenerative diseases in an aging population is an increasing problem of health, social and economic consequences. Epidemiological and intervention studies have demonstrated that diets rich in (poly)phenols can have potent health benefits on cognitive decline and neurodegenerative diseases. Meanwhile, the role of gut microbiota is ever more evident in modulating the catabolism of (poly)phenols to dozens of low molecular weight (poly)phenol metabolites that have been identified in plasma and urine. These metabolites can reach circulation in higher concentrations than parent (poly)phenols and persist for longer periods of time. However, studies addressing their potential brain effects are still lacking. In this review, we will discuss different model organisms that have been used to study how low molecular weight (poly)phenol metabolites affect neuronal related mechanisms gathering critical insight on their potential to tackle the major hallmarks of neurodegeneration.

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo . In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.