Hidradenitis Suppurativa: Where We Are and Where We Are Going

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. It is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture and immune responses. Innate pro-inflammatory cytokines (e.g., IL-1β, and TNF-α); mediators of activated T helper (Th)1 and Th17 cells (e.g., IFN-γ, and IL-17); and effector mechanisms of neutrophilic granulocytes, macrophages, and plasma cells are involved. On the other hand, HS lesions contain anti-inflammatory mediators (e.g., IL-10) and show limited activity of Th22 cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction, and scarring. HS pathogenesis is still enigmatic, and a valid animal model for HS is currently not available. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. Available treatments are limited, mostly off-label, and surgical interventions are often required to achieve remission. In this paper, we provide an overview of the current knowledge surrounding HS, including the diagnosis, pathogenesis, treatments, and existing translational studies.

Animal models of psychosis

The creation of a valid animal model is of crucial importance to the study of the biological mechanisms underlying disease pathophysiology. This becomes difficult when studying psychiatric illness, most especially psychosis, as humans’ mental state is a strictly internally experienced phenomenon, and thus the biological readout of these conditions is often a behavioral assessment. Therefore, when designing appropriate animal model systems and behavioral assessments for the study of psychiatric illness, it is necessary that appropriate measures be taken to ensure the systems and tasks used fulfill rigorous demands of validity. This chapter discusses different forms of validity, expanding on the classical validity measures of face, predictive, and construct validity. Specific examples of behavioral assessments and animal preparations that adhere to these specific definitions of validity are presented. These include specific experimental paradigms that can be similarly assessed in humans with psychosis and animal models, methods to create an animal preparation based on known psychosis triggers and risk factors, and pharmacological means to demonstrate relevance to the human condition. The chapter argues for a systematic approach to design, verify, and validate an animal model system for research into psychosis specifically, and other psychiatric disorders more generally, based on these different classes of validity.

Assessing Attention Orienting in Mice: A Novel Touchscreen Adaptation of the Posner-Style Cueing Task

Atypical attention orienting has been found to be impaired in many neuropsychological disorders, but the underlying neural mechanism remains unclear. Attention can be oriented exogenously (i.e., driven by salient stimuli) or endogenously (i.e., driven by one’s goals or intentions). Genetic mouse models are useful tools to investigate the neurobiology of cognition, but a well-established assessment of attention orienting in mice is missing. This study aimed to adapt the Posner task, a widely used attention orienting task in humans, for use in mice using touchscreen technology and to test the effects of two attention-modulating drugs, methylphenidate (MPH) and atomoxetine (ATX), on the performance of mice during this task. In accordance with human performance, mice responded more quickly and more accurately to validly cued targets compared to invalidly cued targets, thus supporting mice as a valid animal model to study the neural mechanisms of attention orienting. This is the first evidence that mice can be trained to voluntarily maintain their nose-poke on a touchscreen and to complete attention orienting tasks using exogenous peripheral cues and endogenous symbolic cues. The results also showed no significant effects of MPH and ATX on attention orienting, although MPH improved overall response times in mice during the exogenous orienting task. In summary, the current study provides a critical translational task for assessing attention orienting in mice and to investigate the effects of attention-modulating drugs on attention orienting.

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1’s ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

Animal Models for Post-Traumatic Stress Disorder

Animal models of post-traumatic stress disorder (PTSD) provide a wellspring of biological information about this complex condition by providing the opportunity to manipulate trauma exposure and measure biological outcomes in a systematic manner that is not possible in clinical studies. Symptoms of PTSD may be induced in animals by physical (immobilization, foot shock, underwater stress) and psychological stressors (exposure to predator, social defeat, early life trauma) or a combination of both. In addition, genetic, epigenetic and transgenic models have been created by breeding animals with a behavioral propensity for maladaptive stress response or by directly manipulating genes that have been implicated in PTSD. The effect of stressors in animals is measured by a variety of means, including observation of behavior, measurement of structural alterations in the brain and of physiological markers such as HPA axis activity and altered gene expression of central nervous system neurotransmitter system components including receptors. By comparing changes observed in stress exposed animals to humans with PTSD and by comparing animal response to treatments that are effective in humans, we can determine the validity of PTSD animal models. The identification of a reliable physiological marker of maladaptive stress response in animals as well as standard use of behavioral cutoff criteria are critical to the development of a valid animal model of PTSD.

Abstract 400: Statin and Ezetimibe Differently Affect Spontaneous Atherothrombotic Occlusion in a Rabbit Model of Plaque Erosion

Background: Atherothrombosis of a coronary artery with plaque erosion is a major cause of acute coronary syndrome; however, its pathological mechanism and the effects of lipid-lowering therapy are unknown. We have recently reported the CuVIC Trial showing that ezetimibe added to statins improves coronary endothelial function associated with reductions in serum oxysterols in patients after coronary stenting (Takase, et al. ATVB 2017, in press). Methods and Results: We performed balloon injury in iliofemoral arteries in male Japanese white rabbits fed with high cholesterol diet and infused with angiotensin II. We examined the occurrence of atherothrombosis by echography 3 times/week, which were subsequently confirmed by angiography. Histochemical analysis revealed the lack of PECAM1-positive endothelial layer in the atherothrombotic sites. In treatment protocol, animals were divided into 3 groups; 1. Control, 2. Ezetimibe 0.6 mg/kg/day, and 3. Rosuvastatin 1.0 mg/kg/day, resulting total cholesterol 2514+/-179, 1716+/-111, and 1403+/-174, respectively after 8 weeks. Oral treatment with Ezetimibe significantly reduced atherothrombotic occlusion. Although there was no difference in the extent of arterial stenosis among 3 groups, treatment with ezetimibe was associated with better re-endothelialization and less tissue factor (TF)-positive areas in the intima. Serum oxysterols including 7-ketocholesterol (7KC) were lower in the Ezetimibe group. Serum from the model rabbits or 7KC induced TF in cultured SMCs. TF induction by the serum from the Ezetimibe group was significantly less compared with other groups. Conclusions: We established a valid animal model of spontaneous atherothromobotic occlusion in rabbits, which mimicked plaque erosion observed in human coronary arteries. Reduction in serum oxysterols with ezetimibe may prevent atherothrombosis from plaque erosion, by accelerating re-endothelialization and inhibiting TF expression in injured arteries.