TRPV1 Channel in Human Eosinophils: Functional Expression and Inflammatory Modulation.

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel expressed on sensory neurons and immune cells. We hypothesize that TRPV1 plays a role in human eosinophil function and is modulated by inflammatory conditions. TRPV1 expression on human eosinophils was examined by qPCR, flow cytometry, and immunohistochemistry, respectively. TRPV1 functionality was analyzed by investigating calcium flux, apoptosis, modulation by cytokines and acidic pH, and CD69 externalization using flow cytometry. Activation of TRPV1 induced calcium influx and prolonged survival. Although eosinophils were not directly activated by TRPV1 agonists, activation by IL-3 or GM-CSF was mainly restricted to TRPV1-positive eosinophils. TRPV1 surface content was increased by acidic pH, IL-3, IL-31, IL-33, TSLP, TNF-α, BDNF, and NGF-ß. Interestingly, TRPV1 was also expressed by eosinophils located in proximity to peripheral nerves in atopic dermatitis (AD) skin. In conclusion, eosinophils express functional TRPV1 channels which are increased by extracellular acidification and AD-related cytokines. Since eosinophils also express TRPV1 in AD skin, our results indicate an important role of TRPV1 for neuroimmune interaction mechanisms in itchy, inflammatory skin diseases, like AD.

Neurotrophins: Neuroimmune Interactions in Human Atopic Diseases.

Allergic diseases are accompanied by a variety of symptoms such as pruritus, coughing, sneezing, and watery eyes, which can result in severe physiological and even psychological impairments. The exact mechanisms of these conditions are not yet completely understood. However, recent studies demonstrated a high relevance of neurotrophins in allergic inflammation, as they induce cytokine release, mediate interaction between immune cells and neurons, and exhibit different expression levels in health and disease. In this review, we aim to give an overview of the current state of knowledge concerning the role of neurotrophins in atopic disorders such as atopic dermatitis, allergic asthma, and allergic rhinitis.

Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig.

KEY POINTS: C-nociceptors are generally assumed to have a low maximum discharge frequency of 10-30 Hz. However, only mechano-insensitive 'silent' C-nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C-nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation. A distinct class of C-nociceptors with mechanical thresholds >150 mN resembles 'silent' nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. ABSTRACT: Using extracellular single-fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5-100 Hz) in different classes of C-nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano-sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano-insensitive C-nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano-insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C-nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C-fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which possibly contributes to excruciating pain under inflammatory conditions.

Axonal GABAA stabilizes excitability in unmyelinated sensory axons secondary to NKCC1 activity.

KEY POINTS: GABA depolarized sural nerve axons and increased the electrical excitability of C-fibres via GABAA receptor. Axonal excitability responses to GABA increased monotonically with the rate of action potential firing. Action potential activity in unmyelinated C-fibres is coupled to Na-K-Cl cotransporter type 1 (NKCC1) loading of axonal chloride. Activation of axonal GABAA receptor stabilized C-fibre excitability during prolonged low frequency (2.5 Hz) firing. NKCC1 maintains intra-axonal chloride to provide feed-forward stabilization of C-fibre excitability and thus support sustained firing. ABSTRACT: GABAA receptor (GABAA R)-mediated depolarization of dorsal root ganglia (DRG) axonal projections in the spinal dorsal horn is implicated in pre-synaptic inhibition. Inhibition, in this case, is predicated on an elevated intra-axonal chloride concentration and a depolarizing GABA response. In the present study, we report that the peripheral axons of DRG neurons are also depolarized by GABA and this results in an increase in the electrical excitability of unmyelinated C-fibre axons. GABAA R agonists increased axonal excitability, whereas GABA excitability responses were blocked by GABAA R antagonists and were absent in mice lacking the GABAA R ß3 subunit selectively in DRG neurons (AdvillinCre or snsCre ). Under control conditions, excitability responses to GABA became larger at higher rates of electrical stimulation (0.5-2.5 Hz). However, during Na-K-Cl cotransporter type 1 (NKCC1) blockade, the electrical stimulation rate did not affect GABA response size, suggesting that NKCC1 regulation of axonal chloride is coupled to action potential firing. To examine this, activity-dependent conduction velocity slowing (activity-dependent slowing; ADS) was used to quantify C-fibre excitability loss during a 2.5 Hz challenge. ADS was reduced by GABAA R agonists and exacerbated by either GABAA R antagonists, ß3 deletion or NKCC1 blockade. This illustrates that activation of GABAA R stabilizes C-fibre excitability during sustained firing. We posit that NKCC1 acts in a feed-forward manner to maintain an elevated intra-axonal chloride in C-fibres during ongoing firing. The resulting chloride gradient can be utilized by GABAA R to stabilize axonal excitability. The data imply that therapeutic strategies targeting axonal chloride regulation at peripheral loci of pain and itch may curtail aberrant firing in C-fibres.

Transcutaneous Slowly Depolarizing Currents Elicit Pruritus in Patients with Atopic Dermatitis.

Slowly depolarizing currents applied for one minute have been shown to activate C-nociceptors and provoke increasing pain in patients with neuropathy. This study examined the effect of transcutaneous slowly depolarizing currents on pruritus in patients with atopic dermatitis. C-nociceptor-specific electrical stimu-lation was applied to areas of eczema-affected and non-affected skin in 26 patients with atopic dermatitis. Single half-sine wave pulses (500 ms, 0.2-1 mA) induced itch in 9 patients in eczema-affected areas of the skin (numerical rating scale 5 ± 1), but pain in control skin (numerical rating scale 6 ± 1).Sinusoidal stimuli (4 Hz, 10 pulses, 0.025-0.4 mA) evoked itch in only 3 patients in eczema-affected areas of the skin but on delivering pulses for one minute (0.05-0.2 mA) 48% of the patients (n= 12) reported itch with numerical rating scale 4 ± 1 in areas of eczema-affected skin. The number of patients reporting itch in eczema-affected areas of the skin increased with longer stimulation (p < 0.005). These results demonstrate a reduced adaptation of peripheral C-fibres conveying itch in patients with atopic dermatitis. Sensitized spinal itch processing had been suggested before in atopic dermatitis patients, and this could be present also in our patients who therefore might benefit from centrally acting antipruritic therapy.

Chimpanzees return favors at a personal cost.

Humans regularly provide others with resources at a personal cost to themselves. Chimpanzees engage in some cooperative behaviors in the wild as well, but their motivational underpinnings are unclear. In three experiments, chimpanzees (Pan troglodytes) always chose between an option delivering food both to themselves and a partner and one delivering food only to themselves. In one condition, a conspecific partner had just previously taken a personal risk to make this choice available. In another condition, no assistance from the partner preceded the subject's decision. Chimpanzees made significantly more prosocial choices after receiving their partner's assistance than when no assistance was given (experiment 1) and, crucially, this was the case even when choosing the prosocial option was materially costly for the subject (experiment 2). Moreover, subjects appeared sensitive to the risk of their partner's assistance and chose prosocially more often when their partner risked losing food by helping (experiment 3). These findings demonstrate experimentally that chimpanzees are willing to incur a material cost to deliver rewards to a conspecific, but only if that conspecific previously assisted them, and particularly when this assistance was risky. Some key motivations involved in human cooperation thus may have deeper phylogenetic roots than previously suspected.

[Neuropathic pruritus]. / Neuropathischer Pruritus.

In the past 10 years specific pathways for pruritus have been characterized on a cellular and molecular level but their exact role in the pathophysiology of neuropathic pruritus remains unclear. This also applies to the question which of the competing theories for pruritus, e.g. specificity, temporal/spatial pattern or intensity, would best apply. While experimental trials on mice have mostly confirmed the theory of specificity, the results on humans indicate a role of spatial and temporal patterns. The skin innervation is greatly reduced by the neuropathy and could provide a "spatial contrast pattern" and the axotomy could induce a de novo expression of gastrin-releasing peptide (GRP) in primarily afferent nociceptors and thus modulate spinal pruritus processing. In addition, the overlap of pruritus and pain in neuropathy patients complicates the direct translation from animal experiments and requires collaboration at the clinical level between pain medicine and dermatology.

Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain.

OBJECTIVE: Develop and validate a low-intensity sinusoidal electrical stimulation paradigm to preferentially activate C-fibers in human skin. METHODS: Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of "silent" C-nociceptors. Synchronized C-fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small-diameter neurons during transcutaneous 4-Hz stimulation of the hindpaw (0.4mA). RESULTS: Transcutaneous sinusoidal current (0.05-0.4mA, 4Hz) activated "polymodal" C-fibers (50% at ∼0.03mA) and "silent" nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1-ms rectangular pulses ("polymodal" ∼3mA, "silent" ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon-reflex erythema, both indicative of C-nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) -3 and nonpainful skin sites of neuropathic pain patients by NRS -0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2. INTERPRETATION: Sinusoidal electrical stimulation at 4Hz enables preferential activation of C-nociceptors in pig and human skin that accommodates during ongoing (1-minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment. Ann Neurol 2018;83:945-957.

Innovative problem solving in great apes: the role of visual feedback in the floating peanut task.

Nonhuman great apes show remarkable behavioural flexibility. Some individuals are even able to use water as a tool: They spit water into a vertical tube to make a peanut float upwards until it comes into reach (floating peanut task; FPT). In the current study, we used the FPT to investigate how visual feedback, an end-state demonstration and a social demonstration affect task performance in nonhuman great apes in three experiments. Our results indicate that apes who had acquired the solution with a clear tube maintained it with an opaque one. However, apes starting with an opaque tube failed to solve the task. Additionally, facing the peanut floating on a water-filled tube (i.e., an end-state demonstration) promoted success independent on the availability of visual feedback. Moreover, experiencing how water was poured into the tube either by a human demonstrator or by a water tap that had been opened either by the ape or a human did not seem to be of further assistance. First, this study suggests that great apes require visual feedback for solving the FPT, which is no longer required after the initial acquisition. Second, some subjects benefit from encountering the end-state, a finding corroborating previous studies.

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions.

Barrier damage, dry skin and itch are intricately linked and form the basis of many common skin diseases. Damage from environmental insults, or genetic or inflammatory causes, can impair the skin barrier, resulting in an increase in transepidermal water loss and activation of itch-associated nerve fibres. The itch-scratch cycle can perpetuate skin barrier damage and itch. Topical therapeutic strategies are utilised to overcome dry skin and itch, primarily in the form of emollients. Recent advances in our understanding of the mechanisms underlying itch have enabled the development of new topical therapies, which may be incorporated into existing treatment regimes. Ultimately, treatment of dry skin and itch must be highly tailored to the individual according to their needs.

Selective Nerve Fibre Activation in Patients with Generalized Chronic Pruritus: Hint for Central Sensitization?

Central sensitization induces pain augmentation in chronic pain states. An analogous mechanism is speculated for chronic pruritus. This study compared patients with chronic pruritus (n = 79) of different origins (atopic dermatitis, chronic pruritus on non-lesional skin, chronic prurigo) and healthy controls (HC, n = 54) with regard to itch intensity and qualities of sensory symptoms after selective peripheral nerve fibre activation by electrical stimulation at 5 Hz (surrogate for C-fibre function) and 2,000 Hz (surrogate for Aß-fibre function) using a Neurometer®. Electrically-induced itch was more intense in patients with chronic pruritus than in HC, but patients with chronic pruritus did not report "itch" more often than HC at 5 Hz. Stimulation at 2,000 Hz induced more pricking and tingling, but less throbbing in patients with chronic pruritus compared with HC. Treatment with cooling compound reduced clinical and experimental itch, but did not alter the distribution of sensory symptoms. These data show hyperknesis in chronic pruritus of various origins, arguing for common central sensitization mechanisms.

Exploratory Study of Intracutaneous Histamine Stimulation in Patient Populations with Chronic Pruritus.

Chronic pruritus can be a diagnostic sign of an underlying disease. In the intracutaneous histamine test, histamine (one of the best-known inducers of pruritus) may cause different reaction patterns depending on the underlying disease. The aim of this study was to determine if an intracutaneous injection of histamine can differentiate between the causes of chronic pruritus and thus be used as a diagnostic test in chronic pruritus of unknown aetiology. A total of 140 subjects with chronic pruritus with various dermatological, systemic or neurological diseases were included. The intracutaneous histamine test was performed once on each subject. Erythema, wheal and pruritus intensity were measured and analysed. Significantly greater wheal size was observed in patients with systemic or multifactorial causes. In general, there was a significant correlation between age and wheal size. Also, noticeable differences were found between males and females regarding pruritus and wheal size. In summary, the exact type of chronic pruritus could not be clearly determined based on the results of the intracutaneous histamine test. However, the results provide valuable insights into specific reaction patterns to experimental histamine-induced itch, e.g. sex-specific differences in the neurophysiology of pruritus, which should be considered in future studies.

Sensory Qualities Point to Different Structural and Functional Skin Patterns in Chronic Pruritus Patients. A Translational Explorative Study.

Chronic pruritus (CP) is often accompanied by paresthetic sensations like warmth, burning and stinging. The aim of this study was to analyze, whether divergent sensations are linked to structural and functional skin alterations in clinically diagnosed CP patients. Clinical responses to capsaicin, histamine, and to thermal and mechanical stimulation, intraepidermal nerve fiber density, and epidermal expression of transient receptor potential (TRP)-channels were investigated in healthy controls, and in CP patients, reporting either warmth (CP-W) or neuropathic sensations (CP-N). In CP-W, pinprick hyperalgesia and increased sensitivity to capsaicin were aligned with increased epidermal TRPV1 expression, while smaller histamine axon reflex erythema matched with significantly reduced intraepidermal nerve fiber density. CP-N showed earlier onset of sensations after capsaicin stimulation, significantly increased warmth detection threshold, and higher epidermal expression of TRPV4 compared to healthy controls. The present study contributes to the neurobiological understanding of the divergence of sensory sensations in CP, indicating new treatment targets.

Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves.

Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1-NaV1.4, NaV1.6-NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macaca nemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.SIGNIFICANCE STATEMENT It is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve fibers, but clarifying the role of sodium channel subtypes in different axonal segments may be useful for the development of novel analgesic strategies. Here, we provide evidence from mice and nonhuman primates that a substantial portion of the C-fiber compound action potential in distal peripheral nerves, but not proximal nerves or dorsal roots, is resistant to tetrodotoxin and that, in mice, this effect is mediated solely by voltage-gated sodium channel 1.8 (NaV1.8). The functional prominence of NaV1.8 within the axonal compartment immediately proximal to its termination may affect strategies targeting pain of peripheral origin.

Impaired glyoxalase activity is associated with reduced expression of neurotrophic factors and pro-inflammatory processes in diabetic skin cells.

Patients suffering from type II diabetes develop several skin manifestations including cutaneous infections, diabetic dermopathy, diabetic bullae and acanthosis nigricans. Diabetic micro- and macroangiopathy as well as diabetic neuropathy are believed to play a crucial role in the development of diabetic skin disorders. A reduced cutaneous nerve fibre density was reported in diabetic subjects, which subsequently leads to impaired sensory nerve functions. Using an innervated skin model, we investigated the impact of human diabetic dermal fibroblasts and keratinocytes on porcine sensory neurons. Diabetic skin cells showed a reduced capacity to induce neurite outgrowth due to a decreased support with neurotrophic factors, such as NGF. Furthermore, diabetic keratinocytes displayed insulin resistance and increased expression of pro-inflammatory cytokines demonstrating the persistent effect of diabetes mellitus on human skin cells. Dysregulations were related to a significantly reduced glyoxalase enzyme activity in diabetic keratinocytes as experimentally reduced glyoxalase activity mimicked the increase in pro-inflammatory cytokine expression and reduction in NGF. Our results demonstrate an impaired crosstalk of diabetic skin cells and sensory neurons favouring hypo-innervation. We suggest that reduced methylglyoxal detoxification contributes to an impaired neurocutaneous interaction in diabetic skin.

Cognitive test batteries in animal cognition research: evaluating the past, present and future of comparative psychometrics.

For the past two decades, behavioural ecologists have documented consistent individual differences in behavioural traits within species and found evidence for animal "personality". It is only relatively recently, however, that increasing numbers of researchers have begun to investigate individual differences in cognitive ability within species. It has been suggested that cognitive test batteries may provide an ideal tool for this growing research endeavour. In fact, cognitive test batteries have now been used to examine the causes, consequences and underlying structure of cognitive performance within and between many species. In this review, we document the existing attempts to develop cognitive test batteries for non-human animals and review the claims that these studies have made in terms of the structure and evolution of cognition. We argue that our current test battery methods could be improved on multiple fronts, from the design of tasks, to the domains targeted and the species tested. Refining and optimising test battery design will provide many benefits. In future, we envisage that well-designed cognitive test batteries may provide answers to a range of exciting questions, including giving us greater insight into the evolution and structure of cognition.

Cooperative problem solving in giant otters (Pteronura brasiliensis) and Asian small-clawed otters (Aonyx cinerea).

Cooperative problem solving has gained a lot of attention over the past two decades, but the range of species studied is still small. This limits the possibility of understanding the evolution of the socio-cognitive underpinnings of cooperation. Lutrinae show significant variations in socio-ecology, but their cognitive abilities are not well studied. In the first experimental study of otter social cognition, we presented two species-giant otters and Asian small-clawed otters-with a cooperative problem-solving task. The loose string task requires two individuals to simultaneously pull on either end of a rope in order to access food. This task has been used with a larger number of species (for the most part primates and birds) and thus allows for wider cross-species comparison. We found no differences in performance between species. Both giant otters and Asian small-clawed otters were able to solve the task successfully when the coordination requirements were minimal. However, when the temporal coordination demands were increased, performance decreased either due to a lack of understanding of the role of a partner or due to difficulty inhibiting action. In conclusion, two species of otters show some ability to cooperate, quite similar to most other species presented with the same task. However, to draw further conclusions and more nuanced comparisons between the two otter species, further studies with varied methodologies will be necessary.

Distraction From Itch Shows Brainstem Activation Without Reduction in Experimental Itch Sensation.

The central processing of itch is not completely understood. This is the first study to use functional magnetic resonance imaging (fMRI) to examine the central modulation by distraction of experimentally induced itch. A total of 33 healthy volunteers were examined with fMRI. Periods of itch induction without distraction and itch with distraction by a Stroop task (psychological test, where the participants have to decide if the colour of the writing corresponds to the written word, for example if "red" is written in red or not) were counterbalanced during the scanning to examine task-specific changes in blood oxygenation level dependent-signal. The intensity of the subjects' itch sensation, desire to scratch and pain sensation were evaluated. Distraction by a Stroop task did not reduce itch intensity or urge to scratch. However, the Stroop task led to significantly higher activation of the left brainstem when it followed the "pure" itch sensation. Itch and pain seem to have similar inhibition pathways, particularly concerning brainstem activation during distraction. But as itch sensation, in contrast to pain, could not be sufficiently reduced by distraction, both entities might have different modulation systems.

Differing views: Can chimpanzees do Level 2 perspective-taking?

Although chimpanzees understand what others may see, it is unclear whether they understand how others see things (Level 2 perspective-taking). We investigated whether chimpanzees can predict the behavior of a conspecific which is holding a mistaken perspective that differs from their own. The subject competed with a conspecific over two food sticks. While the subject could see that both were the same size, to the competitor one appeared bigger than the other. In a previously established game, the competitor chose one stick in private first and the subject chose thereafter, without knowing which of the sticks was gone. Chimpanzees and 6-year-old children chose the 'riskier' stick (that looked bigger to the competitor) significantly less in the game than in a nonsocial control. Children chose randomly in the control, thus showing Level 2 perspective-taking skills; in contrast, chimpanzees had a preference for the 'riskier' stick here, rendering it possible that they attributed their own preference to the competitor to predict her choice. We thus run a follow-up in which chimpanzees did not have a preference in the control. Now, they also chose randomly in the game. We conclude that chimpanzees solved the task by attributing their own preference to the other, while children truly understood the other's mistaken perspective.

Facial Erythema of Rosacea - Aetiology, Different Pathophysiologies and Treatment Options.

Rosacea is a common chronic skin condition that displays a broad diversity of clinical manifestations. Although the pathophysiological mechanisms of the four subtypes are not completely elucidated, the key elements often present are augmented immune responses of the innate and adaptive immune system, and neurovascular dysregulation. The most common primary feature of all cutaneous subtypes of rosacea is transient or persistent facial erythema. Perilesional erythema of papules or pustules is based on the sustained vasodilation and plasma extravasation induced by the inflammatory infiltrates. In contrast, transient erythema has rapid kinetics induced by trigger factors independent of papules or pustules. Amongst the current treatments for facial erythema of rosacea, only the selective α2-adrenergic receptor agonist brimonidine 0.33% topical gel (Mirvaso®) is approved. This review aims to discuss the potential causes, different pathophysiologies and current treatment options to address the unmet medical needs of patients with facial erythema of rosacea.