Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

Introduction Neutrophils are the primary effectors of the innate immune system but are profoundly histotoxic cells. The acute respiratory distress syndrome (ARDS) is considered to be a prime example of neutrophil-mediated tissue injury. Sources of data The information presented in this review is acquired from the published neutrophil cell biology literature and the longstanding interest of the senior authors in ARDS pathogenesis and clinical management. Areas of agreement Investigators in the field would agree that neutrophils accumulate in high abundance in the pulmonary microcirculation, lung interstitium and alveolar airspace of patients with ARDS. ARDS is also associated with systemic neutrophil priming and delayed neutrophil apoptosis and clearance of neutrophils from the lungs. In animal models, reducing circulating neutrophil numbers ameliorates lung injury. Areas of controversy Areas of uncertainty include how neutrophils get stuck in the narrow pulmonary capillary network—whether this reflects changes in the mechanical properties of primed neutrophils alone or additional cell adhesion molecules, the role of neutrophil sub-sets or polarization states including pro-angiogenic and low-density neutrophils, whether neutrophil extracellular trap (NET) formation is beneficial (through bacterial capture) or harmful and the potential for neutrophils to participate in inflammatory resolution. The latter may involve the generation of specialized pro-resolving molecules (SPMs) and MMP-9, which is required for adequate matrix processing. Growing points Different and possibly stable endotypes of ARDS are increasingly being recognized, yet the relative contribution of the neutrophil to these endotypes is uncertain. There is renewed and intense interest in understanding the complex ‘new biology’ of the neutrophil, specifically whether this cell might be a valid therapeutic target in ARDS and other neutrophil-driven diseases and developing understanding of ways to enhance the beneficial role of the neutrophil in the resolution phase of ARDS. Areas timely for developing research Aside from treatment of the precipitating causes of ARDS, and scrupulous fluid, infection and ventilation management, there are no pharmacological interventions for ARDS; this represents an urgent and unmet need. Therapies aimed at reducing overall neutrophil numbers risk secondary infection; hence better ways are needed to reverse the processes of neutrophil priming activation, hyper-secretion and delayed apoptosis while enhancing the pro-resolution functions of the neutrophil.

It has become increasingly apparent that the biomechanical properties of neutrophils impact on their trafficking through the circulation and in particularly through the pulmonary capillary bed. The retention of polarized or shape‐changed neutrophils in the lungs was recently proposed to contribute to acute respiratory distress syndrome pathogenesis. Accordingly, this study tested the hypothesis that neutrophil priming is coupled to morpho‐rheological (MORE) changes capable of altering cell function. We employ real‐time deformability cytometry (RT‐DC), a recently developed, rapid, and sensitive way to assess the distribution of size, shape, and deformability of thousands of cells within seconds. During RT‐DC analysis, neutrophils can be easily identified within anticoagulated “whole blood” due to their unique granularity and size, thus avoiding the need for further isolation techniques, which affect biomechanical cell properties. Hence, RT‐DC is uniquely suited to describe the kinetics of MORE cell changes. We reveal that, following activation or priming, neutrophils undergo a short period of cell shrinking and stiffening, followed by a phase of cell expansion and softening. In some contexts, neutrophils ultimately recover their un‐primed mechanical phenotype. The mechanism(s) underlying changes in human neutrophil size are shown to be Na+/H+ antiport‐dependent and are predicted to have profound implications for neutrophil movement through the vascular system in health and disease.

Emerging evidence suggests a complex relationship between sphingosine 1-phosphate (S1P) signaling and stroke. Here, we show the kinetics of S1P in the acute phase of ischemic stroke and highlight accompanying changes in immune cells and S1P receptors (S1PR). Using a C57BL/6 mouse model of middle cerebral artery occlusion (MCAO), we assessed S1P concentrations in the brain, plasma, and spleen. We found a steep S1P gradient from the spleen towards the brain. Results obtained by qPCR suggested that cells expressing the S1PR type 1 (S1P1+) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (TH) and regulatory T (TREG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1PR expression patterns in the brain after MCAO. This study provides insight that the S1P-S1PR axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1PR+ TH and TREG cells. Further insights by which means the S1P-S1PR-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.