A hassle a day may keep the doctor away: stress and the augmentation of immune function

Stress may be defined as a sequence of events, that begins witha stimulus (stressor), that is recognized by the brain (stressperception), and which results in the activation of physiologicfight/flight/fright systems within the body (stress response).Many evolutionary selection pressures are stressors, and oneof the primary functions of the brain is to perceive stress,warn the body of danger, and enable an organism to respond.We hypothesized that under acute conditions, just as the stressresponse prepares the cardiovascular and musculoskeletal systemsfor fight or flight, it may also prepare the immune system forchallenges (e.g., wounding) which may be imposed by a stressor(e.g., an aggressor). Initial studies showed that acute (2h)stress induced a significant trafficking of immune cells tothe skin. Since the skin is an organism's major protective barrier,we hypothesized that this leukocyte redistribution may serveto enhance skin immunity during acute stress. We tested thishypothesis using the delayed type hypersensitivity (DTH) reaction,which mediates resistance to various infectious agents, as amodel for skin immune function. Acute stress administered immediatelybefore antigen exposure significantly enhanced skin DTH. Adrenalectomy(ADX) eliminated the stress-induced enhancement of DTH whileadministration of physiological doses of corticosterone and/orepinephrine to ADX animals enhanced skin DTH in the absenceof stress. These studies showed that changes in leukocyte distributionand circulating stress hormones are systemic mediators of theimmunoenhancing effects of acute stress. We recently identifiedgamma interferon as a local cytokine mediator of a stress-inducedimmunoenhancement. Our results suggest that during acute stressthe brain sends preparatory warning signals to the immune systemjust as it does to other fight/flight systems of the body.     

The skin of fish as a transport epithelium: a review

The primary function of fish skin is to act as a barrier. It provides protection against physical damage and assists with the maintenance of homoeostasis by minimising exchange between the animal and the environment. However in some fish, the skin may play a more active physiological role. This is particularly true in species that inhabit specialised environmental niches (e.g. amphibious and air-breathing fish such as the lungfish), those with physiological characteristics that may subvert the need for the integument as a barrier (e.g. the osmoconforming hagfish), and/or fish with anatomical modifications of the epidermis (e.g. reduced epithelial thickness). Using examples from different fish groups (e.g. hagfishes, elasmobranchs and teleosts), the importance of fish skin as a transport epithelium for gases, ions, nitrogenous waste products, and nutrients was reviewed. The role of the skin in larval fish was also examined, with early life stages often utilising the skin as a surrogate gill, prior to the development of a functional branchial epithelium.     

Sebocytes,multifaceted epithelial cells: Lipid production and holocrine secretion

Sebocytes are highly specialized, sebum-producing epithelial cells that release their content by rupture of the cell membrane and cellular degradation (holocrine secretion). These cells are most commonly found in the skin in association with hair follicles (forming the pilosebaceous unit), where they arise from hair follicle keratinocytes, but there are also sebaceous glands (SGs) not associated with a hair follicle. The latter have special functions as secretion of pheromones or corneal protection. While the full range of sebum functions in human skin remains to be clarified, sebum forms an integral component of the epidermal barrier and the skin immune system. Sebocyte formation is controlled by multiple molecular pathways (e.g. Blimp1, Wnt, C-myc, Hedgehog) and sebum synthesis is strongly regulated by hormones, in particular by androgens. Excessive sebum production is seen in acne vulgaris, one of the most common skin diseases, while deregulated sebocyte differentiation characterizes some rare benign and malignant tumors.     

Immunization with DNA through the skin

The skin has evolved as a barrier to prevent external agents, including pathogens, from entering the body. It has a complex and efficient immune surveillance system, which includes Langerhans cells and dendritic cells. By targeting the body's natural defense system, skin-DNA immunization attempts to produce an efficient immune response. Nucleic acid vaccines provide DNA for protein expression in a variety of cells, including keratinocytes, Langerhans cells, and dendritic cells, which are located in the two main areas of the skin, the epidermis (the most superficial layer) and the dermis. After maturation, Langerhans cells and dermal dendritic cells can migrate to local lymph nodes where presentation of antigens to T cells can occur and thus start a variety of immunologic responses. Dermal immunization methods described in this article target the epidermis, the dermis, or both and include: (a) stripping; (b) chemical modification; (c) trans-epidermal immunization (transcutaneous immunization or non-invasive vaccination of the skin); (d) gene gun technology; (e) electroporation; (f) intradermal injections; and (g) microseeding. These techniques all require the removal of hair, the circumvention or modification of the stratum corneum layer of the epidermis, and the addition of DNA or amplification of DNA signal. As the biology of the skin and the mechanisms of DNA vaccination are elucidated, these skin immunization techniques will be optimized. With refinement, skin-DNA immunization will achieve the goal of producing a reliable and efficacious immune response to a variety of pathogens.     

Corticotropin releasing hormone and its function in the skin.

The skin, as the largest organ of the body, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stressors such as bursts of radiation (solar, thermal), mechanical energy, or chemical and biological insults. Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for dealing with the stressors. Activities of the skin are mostly regulated by local cutaneous factors and stressed skin can generate signals to produce rapid (neural) or slow (humoral) responses to local or systemic levels. Thus, the skin neuroendocrine system is comprised of locally produced neuroendocrine mediators that interact with corresponding specific receptors through para- or autocrine mechanisms. Furthermore, it is known for several years that the corticotropin-releasing hormone (CRH)/ pro-opiomelanocorticotropin (POMC) skin system fulfils analogous functions to the hypothalamic-pituitary-adrenal (HPA) stress axis. Additionally, skin cells produce hormones, neurotansmitters and neuropeptides, having the corresponding receptors and the skin itself is able to fulfill a multidirectional communication between endocrine, immune and central nervous systems as well as other internal organs. In summary, the skin expresses an equivalent of the prominent hypothalamic-pituitary-adrenal stress axis that may act as a cutaneous defense system, operating as a coordinator and executor of local responses to stress, in addition to its normal function: the preservation of body homeostasis.     

Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy

The rather thin outermost layer of the mammalian skin, stratum corneum (SC), is a complex biomembrane which separates the water rich inside of the body from the dry outside. The skin surface can be exposed to rather extreme variations in ambient conditions (e.g. water activity, temperature and pH), with potential effects on the barrier function. Increased understanding of how the barrier is affected by such changes is highly relevant for regulation of transdermal uptake of exogenous chemicals. In the present study we investigate the effect of hydration and the use of a well-known humectant, urea, on skin barrier ultrastructure by means of confocal Raman microspectroscopy. We also perform dynamic vapor sorption (DVS) microbalance measurements to examine the water uptake capacity of SC pretreated with urea. Based on novel Raman images, constructed from 2D spectral maps, we can distinguish large water inclusions within the skin membrane exceeding the size of fully hydrated corneocytes. We show that these inclusions contain water with spectral properties similar to that of bulk water. The results furthermore show that the ambient water activity has an important impact on the formation of these water inclusions as well as on the hydration profile across the membrane. Urea significantly increases the water uptake when present in skin, as compared to skin without urea, and it promotes formation of larger water inclusions in the tissue. The results confirm that urea can be used as a humectant to increase skin hydration.     

Alcohol ingestion before burn injury decreases splanchnic blood flow and oxygen delivery

Recent studies from our laboratory have shown that alcohol and burn injury impair intestinal barrier and immune functions. Although multiple factors can contribute to impaired intestinal barrier function, such an alteration could result from a decrease in intestinal blood flow (BF) and oxygen delivery (DO2). Therefore, in this study, we tested the hypothesis that alcohol ingestion before burn injury reduces splanchnic blood flow and oxygen delivery. Rats (250 g) were gavaged with alcohol to achieve a blood ethanol level in the range of 100 mg/dl before burn or sham injury (25% total body surface area). Day 1 after injury, animals were anesthetized with methoxyflurane. Blood pressure, cardiac output (CO), +/-dP/dt, organ BF (in ml.min(-1).100 g(-1)), and DO2 (in mg.ml(-1).100 g(-1)) were determined. CO and organ BF were determined using a radioactive microsphere technique. Our results indicate that blood pressure, CO, and +dP/dt were decreased in rats receiving a combined insult of alcohol and burn injury compared with rats receiving either burn injury or alcohol alone. This is accompanied by a decrease in BF and DO2 to the liver and intestine. No significant change in BF to the coronary arteries (heart), brain, lung, skin, and muscles was observed after alcohol and burn injury. In conclusion, the results presented here suggest that alcohol ingestion before burn injury reduces splanchnic BF and DO2. Such decreases in BF and DO2 may cause hypoxic insult to the intestine and liver. Although a hypoxic insult to the liver would result in a release of proinflammatory mediators, a similar insult to the intestine will likely perturb both intestinal immune cell and barrier functions, as observed in our previous study.     

Prolongation of skin allograft survival after neonatal injection of donor bone marrow and epidermal cells

Composite-tissue (e.g., hand allograft) allotransplantation is currently limited by the need for immunosuppression to prevent graft rejection. Inducing a state of tolerance in the recipient could potentially eliminate the need for immunosuppression but requires reprogramming of the immunological repertoire of the recipient. Skin is the most antigenic tissue in the body and is consistently refractory to tolerance induction regimens using bone marrow transplantation alone. It was hypothesized that tolerance to skin allografts could be induced in rats by injecting epidermal cells with bone marrow cells during the first 24 hours of life of the recipients. Brown Norway rats (RT1n) served as donors for the epidermal cells, bone marrow cells, and skin grafts. Epidermal cells were injected intraperitoneally and bone marrow cells were injected intravenously into Lewis (RT1l) newborn recipient rats. In control groups, recipients received saline solution with no cells (group I, n = 12), bone marrow cells only (group II, n = 15), or epidermal cells only (group III, n = 15). In the experimental group (group IV, n = 18), recipients received epidermal and bone marrow cells simultaneously. Skin grafts were transplanted from Brown Norway (RT1n) rats to the Lewis (RT1l) rats 8 weeks after cell injections. Skin grafts survived an average of 8.5 days in group I (10 grafts), 9.2 days in group II (12 grafts), and 12 days in group III (14 grafts). Grafts survived 15.5 days (8 to 26 days) in group IV (15 grafts). The difference was statistically significant (p < 0.05). Hair growth was observed in some accepted grafts in group IV but never in the control groups. This is the first report of prolonged survival of skin allografts in a rat model after epidermal and bone marrow cell injections. Survival prolongation was achieved across a major immunological barrier, without irradiation, myeloablation, or immunosuppression. It is concluded that the presentation of skin-specific antigens generated a temporary state of tolerance to the skin in the recipients that could have delayed the rejection of skin allografts.     

Special feature for the Olympics: effects of exercise on the immune system: exercise effects on systemic immunity

Heavy exertion has acute and chronic influences on systemic immunity. In the resting state, the immune systems of athletes and non-athletes are more similar than disparate with the exception of NK cell activity, which tends to be elevated in athletes. Many components of the immune system exhibit adverse change after prolonged, heavy exertion. These immune changes occur in several compartments of the immune system and body (e.g. the skin, upper respiratory tract mucosal tissue, lung, blood and muscle). Although still open to interpretation, most exercise immunologists believe that during this 'open window' of impaired immunity (which may last between 3 and 72 h, depending on the immune measure) viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. The infection risk may be amplified when other factors related to immune function are present, including exposure to novel pathogens during travel, lack of sleep, severe mental stress, malnutrition or weight loss.     

Allometry of thermal limitation in the cephalopod Sepia officinalis

Cuttlefish (Sepia officinalis) routine metabolic rate was determined in response to acute thermal changes at a rate of 1 degrees C h(-1) for a variety of animal sizes (15-496 g wet mass, laboratory reared at 15 degrees C). In a thermal frame of 11 to 23 degrees C, oxygen consumption rates (MO(2), in mumol O(2) g(-1) min(-1)) were observed to rise with increasing temperature (T, in degrees C) and to decline with increasing body mass (m, in g), according to the formula: ln MO(2)=-3.3+0.0945T-0.215 ln m (R(2)=0.93). Outside the above thermal window, animals were not able to increase MO(2) at similar rates, indicating a beginning oxygen limitation of metabolism. Large animals (>100 g body mass) already displayed lower than expected MO(2) values at 8 and 26 degrees C, while smaller animals (15 g wet mass) were characterized by a wider thermal window (MO(2) values deviated from expected rates at 5 and 29 degrees C). Morphometric data of cuttlefish mantle skin area was obtained to discuss size - related effects of skin respiration potential on thermal tolerance. Cuttlefish growth was observed to be isometric, as constant 'Vogel numbers' of 4.2 indicated (animal body masses: 11 to 401 g). In the same mass range, specific mantle surface area declined three-fold from 10.7 (0.24) (means+/-SD) to 3.3 (0.52) cm(2) g(-1). Thus, increased thermal tolerance in smaller animals may be enabled by a higher skin respiration potential due to higher specific skin surface areas. An elevated fraction of MO(2) provided by means of skin respiration in small animals could relieve the cardiovascular system, which previously has been found a major limiting component during acute thermal stress in cuttlefish.     

益生菌对皮肤光老化的修复作用及其机制研究进展

皮肤是人体最大的器官,也是机体防御外界各种物理、化学及病原微生物侵害的重要组织.皮肤系统若出现老化,则导致其功能衰退、防御功能下降,危害机体健康.日常生活中,各类光照时刻侵害着我们的皮肤,加速其老化的速度.研究指出,光照尤其是日光中的紫外辐射可通过直接损伤DNA、产生活性氧、降解细胞外基质和诱发炎症等多种方式损伤皮肤细...     

The importance of the neuro‐immuno‐cutaneous system on human skin equivalent design

The skin is a highly complex organ, responsible for sensation, protection against the environment (pollutants, foreign proteins, infection) and thereby linked to the immune and sensory systems in the neuro‐immuno‐cutaneous (NIC) system. Cutaneous innervation is a key part of the peripheral nervous system; therefore, the skin should be considered a sensory organ and an important part of the central nervous system, an ‘active interface’ and the first connection of the body to the outside world. Peripheral nerves are a complex class of neurons within these systems, subsets of functions are conducted, including mechanoreception, nociception and thermoception. Epidermal and dermal cells produce signalling factors (such as cytokines or growth factors), neurites influence skin cells (such as via neuropeptides), and peripheral nerves have a role in both early and late stages of the inflammatory response. One way this is achieved, specifically in the cutaneous system, is through neuropeptide release and signalling, especially via substance P (SP), neuropeptide Y (NPY) and nerve growth factor (NGF). Cutaneous, neuronal and immune cells play a central role in many conditions, including psoriasis, atopic dermatitis, vitiligo, UV‐induced immunosuppression, herpes and lymphomas. Therefore, it is critical to understand the connections and interplay between the peripheral nervous system and the skin and immune systems, the NIC system. Relevant in vitro tissue models based on human skin equivalents can be used to gain insight and to address impact across research and clinical needs.     

Constitutive production of lymphocyte activating factors by normal tissues in the adult rat

Lymphocyte activating factors (LAFs), e.g., interleukin-1 (IL-1) and IL-1-like factors, have previously been demonstrated outside the immune system in the skin, thymus epithelium, and the human and rat testis. We have studied the presence of LAFs in normal tissues of the adult rat, utilizing a highly IL-1 sensitive murine thymocyte proliferation assay. We have demonstrated high amounts of LAF activity in the tongue, esophagus, proventricular part of the stomach, and the liver. Some activity was also demonstrated in the duodenum, placenta, spleen, Peyer's patches, glandular stomach, and jejunum, but no bioactivity was present in other gastrointestinal, endocrine, lymphoid, or haematopoeitic tissues. We were also unable to detect any LAF activity in the reproductive organs (except for the testis), urinary tract, skeletal and muscular tissues, brain, eyes, salivary glands, or lung. In the esophagus the activity was mainly localized to the mucosa. The LAF activity in the skin was partly inhibited by treatment with a mixture of antibodies against human IL-1 alpha and IL-1 beta. Dose response curves and gel filtration on a Sephacryl S-200 column suggested the presence of a high molecular weight (90,000-100,000 Da) LAF inhibitory factor in the liver. In all positive tissues, the demonstrated LAFs had a molecular weight of 15,000-25,000 Da, as determined by Sephacryl S-200 gel filtration. Of the positive tissues, the skin, tongue, esophagus, and the proventricular part of the stomach all contain stratified squamous epithelium. It is tempting to suggest that the detected LAFs have a similar function in these barrier tissues, e.g., to serve as host defence factors, or, alternatively or additionally, as tissue growth factors.     

Innate antimicrobial peptides in the skin

Human skin is always in contact with the environment and is covered with a characteristic microflora, but it is usually not infected. Although desquamation and secretion of mucus lead to a permanent renewal of these body surfaces and simultaneous elimination of microorganisms adhering to these layers, another reason for this natural resistance might be the existence of a "chemical barrier" consisting in constitutively and inducibly produced antimicrobial peptides and proteins (AMPs), which include some ss-defensins, RNase 7, the S100-protein psoriasin and the cathelicidin LL-37. Most of these AMPs can be induced in vitro in epithelial cells by proinflammatory cytokines or bacteria. In vivo, AMPs are mainly expressed in uppermost and differentiated parts of inflammatory lesions and wounds, but some are also focally expressed in skin in the absence of inflammation, suggesting that apart from inflammatory mediators, also non-inflammatory stimuli of endogenous and/or exogenous origin can stimulate AMP-synthesis. Increased levels of AMPs in psoriatic lesions may explain why psoriasis patients rarely suffer from skin infections. Further, an increased infection rate in atopic dermatitis patients could be the consequence of decreased levels of AMPs in atopic lesions. These observations may indicate an important role of the "chemical skin barrier" in prevention of skin infection and suggest that artificial stimulation of this system, without inflammation, would be beneficial as "immune stimulus".     

The skin as interface in the transmission of arthropod-borne pathogens

Animal skin separates the inner world of the body from the largely hostile outside world and is actively involved in the defence against microbes. However, the skin is no perfect defence barrier and many microorganisms have managed to live on or within the skin as harmless passengers or as disease-causing pathogens. Microbes have evolved numerous strategies that allow them to gain access to the layers underneath the epidermis where they either multiply within the dermis or move to distant destinations within the body for replication. A number of viruses, bacteria and parasites use arthropod vectors, like ticks or mosquitoes, to deliver them into the dermis while taking their blood meal. Within the dermis, successful pathogens subvert the function of a variety of skin resident cells or cells of the innate immune system that rush to the site of infection. In this review several interactions with cells of the skin by medically relevant vector-borne pathogens are discussed to highlight the different ways in which these pathogens have come to survive within the skin and to usurp the defence mechanisms of the host for their own ends.     

无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症中的应用

摘要 目的：探讨无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)中的应用价值。方法：研究时间为2017年1月到2020年12月,选择在本院诊治的朗格汉斯细胞组织细胞增多症患者72例作为LCH组,同期选择健康体检者72例作为对照组。采用无创性皮肤屏障功能检测皮肤水分、经皮水分丢失(Transdermal water loss,TEWL)、油脂水平,同时检测所有入选者的免疫功能、皮肤菌群并进行相关性分析。结果：LCH组的皮肤水分低于对照组(P<0.05),TEWL、油脂水平高于对照组(P<0.05)。LCH组的乳酸杆菌(La)阳性率低于对照组(P<0.05),表皮葡萄球菌(Se)、痤疮丙酸杆菌(Pa)、金黄色葡萄球菌(Sa)阳性率高于对照组(P<0.05)。LCH组的CD163、ki-67表达阳性率分别为77.8 %、52.8 %,高于对照组的19.4 %和6.9 %(P<0.05)。在LCH组中,Pearson相关性分析显示皮肤水分与乳酸杆菌呈现正相关性(P<0.05),TEWL、油脂与表皮葡萄球菌、痤疮丙酸杆菌、金黄色葡萄球菌、CD163、ki-67呈现正相关性(P<0.05)。结论：无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症中的应用可反映患者的皮肤水分与油脂状况,也可间接反映患者的皮肤微生态与免疫功能状况。     

Vascular endothelial insulin/IGF-1 signaling controls skin wound vascularization

Type 2 diabetes mellitus affects 6% of western populations and represents a major risk factor for the development of skin complications, of which impaired wound healing, manifested in e.g. "diabetic foot ulcer", is most prominent. Impaired angiogenesis is considered a major contributing factor to these non-healing wounds. At present it is still unclear whether diabetes-associated wound healing and skin vascular dysfunction are direct consequences of impaired insulin/IGF-1 signaling, or secondary due to e.g. hyperglycemia. To directly test the role of vascular endothelial insulin signaling in the development of diabetes-associated skin complications and vascular function, we inactivated the insulin receptor and its highly related receptor, the IGF-1 receptor, specifically in the endothelial compartment of postnatal mice, using the inducible Tie-2CreERT (DKO(IVE)) deleter. Impaired endothelial insulin/IGF-1 signaling did not have a significant impact on endothelial homeostasis in the skin, as judged by number of vessels, vessel basement membrane staining intensity and barrier function. In contrast, challenging the skin through wounding strongly reduced neo-angiogenesis in DKO(IVE) mice, accompanied by reduced granulation tissue formation reduced. These results show that endothelial insulin/IGF signaling is essential for neo-angiogenesis upon wounding, and imply that reduced endothelial insulin/IGF signaling directly contributes to diabetes-associated impaired healing.     

Sea snake skin: Permeable to water but not to sodium

Summary Fasting yellow-bellied sea snakes (Pelamis) have a very low rate of exchange of Na with sea water. Influx and efflux are balanced at a value near 8 moles/100 g h. This is only a fraction of the rate of exchange found in marine fish. Na influx is due to uptake in the head region; dermal and cloacal influx are minimal. The impermeability of the skin to Na has been confirmed in isolated preparations. The outer keratin layer seems to be the primary barrier, since the shed skin alone is also impermeable. Na efflux can be increased to 140 m/100 g h by salt injections, and secretion by the sublingual salt gland can account for all of this loss. Fasting snakes are not in water balance in sea water. There is a net loss of water amounting to about 0.4% body wt/day that probably occurs mainly through the skin. The major osmotic problem ofPelamis in sea water seems to be water balance, not salt balance. Differences in salt gland size among sea snakes might be related to differences in skin permeability to water associated with dermal respiration. The importance of the skin as a permeability barrier suggests that the frequent skin shedding of sea snakes may be related to maintenance of low water permeability as well as to prevention of growth by marine fouling organisms.