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Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1β-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1β-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders.

The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization's and National Institutes of Health's high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host's vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, and CPKP. We show that the pharmacological inhibition of ARF6-GTP phenocopies endothelium-specific Arf6 disruption in enhancing the survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small-molecule inhibitors acts by the restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of the TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host's vasculature with small-molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and reemerging pathogens.

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy., Introduction Over 25 million people in the United States have diabetes mellitus (1) and are prone to suffer from its devastating sequelae. The metabolic derangements seen in diabetes lead to [...]

The activation of the small GTPase ARF6 has been implicated in promoting several pathological processes related to vascular instability and tumor formation, growth, and metastasis. ARF6 also plays a vital role during embryonic development. Recent studies have suggested that ARF6 carries out these disparate functions primarily by controlling protein trafficking within the cell. ARF6 helps direct proteins to intracellular or extracellular locations where they function in normal cellular responses during development and in pathological processes later in life. This transport of proteins is accomplished through a variety of mechanisms, including endocytosis and recycling, microvesicle release, and as yet uncharacterized processes. This Commentary will explore the functions of ARF6, while focusing on the role of this small GTPase in development and postnatal physiology, regulating barrier function and diseases associated with its loss, and tumor formation, growth, and metastasis. [ABSTRACT FROM AUTHOR]

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We sought to understand the consequences itchiness has on daily life that may not be immediately obvious in clinical assessments for patients with atopic dermatitis (AD). METHODS: Focus groups and interviews involving 21 patients with AD and 12 family members examined aspects of the effects of itchiness on health-related quality of life (HRQL). Investigators conducted a thematic analysis where two researchers independently coded the narratives and arrived at a consensus on major themes. RESULTS: Five themes emerged from our discussions. 1) Miserable experience: Itchiness was difficult to control and cease. 2) Physical damage: Damage to skin and hair occurred from scratching to alleviate the itchiness. 3) Effects on daily activities: Itchiness could affect everything participants did, including how they dressed, used make-up, and slept. 4) Effects on social activities and relationships: The discomfort and embarrassment from scratching in public and others' reactions hindered participants' social lives. 5) Emotional consequences: Various emotional responses to itchiness were reported, including embarrassment, depression, and irritation.LIMITATIONS: Though qualitative research provides a level of detail not often found in quantitative analyses, this study design is limited by small sample size and generalizability. CONCLUSION: Understanding these challenges can help clinicians open deeper conversations with their patients to learn more about what patients need from their dermatologic care. While itchiness from AD is well-known, this study shows that its effects on HRQL are not minimal and that patients may need further care for the consequences of this symptom. [ABSTRACT FROM AUTHOR]

Background: Pruritus is the most common symptom of psoriasis, with a significant impact on patient quality of life. In spite of this, the severity, persistence, and overall impact of itchiness has only been rarely formally assessed during standard psoriasis clinic visits. Objectives: We sought to understand the far-reaching impacts of itchiness on the lives of those with psoriasis and their families.Methods: We conducted a qualitative study with five focus groups and 10 semi-structured interviews from August 2018 to January 2019. We enrolled 25 individuals with a diagnosis of at least moderate plaque psoriasis and 11 family members (primarily significant others). Views and experiences were analyzed thematically via content analysis.Results: Itchiness considerably impacts those with plaque psoriasis and their families. Our narrative analysis produced three main themes relating to itchiness: the triggers of itchiness, including climate, emotions, and behaviors; the physical consequences of itchiness, including disruption of emotional well-being, sleep disturbance, and daily activities; and the prevention and treatment strategies used to alleviate itchiness.Conclusion: Itchiness impacts the quality of life in those with psoriasis and their family members. We strongly urge clinicians to inquire about and monitor the severity and impact of itchiness in psoriasis patients. [ABSTRACT FROM AUTHOR]