Mehdi Sakka

TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization

ABSTRACTCutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

The presence of monoclonal gammopathy in Ph-negative myeloproliferative neoplasms is associated with a detrimental effect on outcomes

Abstract Many case reports have indicated the occurrence of monoclonal gammopathy of uncertain significance (MGUS) or multiple myeloma (MM) in patients with Ph-negative myeloproliferative neoplasms (MPN), but few cohorts of patients have been published. This study concerns 667 patients newly diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) who were tested for monoclonal (M) protein at diagnosis (13.9% of patients). The overall survival of patients with M protein was dramatically lower than that of patients without M protein (12.7 versus 22.4 years; p = .0132). Univariate analysis identified the presence of M protein as a potential risk factor for the secondary occurrence of myelofibrosis (p = .02), myelodysplastic syndrome (p = .043), and MM/Waldenstrom macroglobulinemia (p < .0001). Our cohort shows that the presence of M proteins in patients with PV or ET leads to a poor prognosis. We believe that testing for M protein could help practicians to identify such patients.

In vitro models to study cutaneous innervation mechanisms

The skin is densely innervated to transmit all sensations (touch, temperature, pressure, pain, and pruritus) but not only it. Indeed, innervation plays a major role in the structuration of the epidermis, in its renewal, and in the process as wound healing. There are increasing evidences that skin cells and cutaneous nerve endings are in close interactions each other. So, to study them is an important issue to better understand the behavior of the skin and its both physiological and pathological processes. However, due to scientific, technical, ethical, or economic reasons, the study of these interactions in human or animals in vivo remains quite impossible. So, the development of in vitro models is crucial to better understand them. Since several years, all the actors of these interactions, skin cells such as keratinocytes, fibroblasts, melanocytes, Merkel cells or stem cells, and sensory neurons, could be extracted and cultured independently or together so named 2-D cocultures. Other cocultures, the 3-D cocultures, could also be considered by the use of the epidermis or dermis or whole portions of native or reconstructed skin. These 3-D models offer also an alternative by the use of compartmented cocultures to only analyze the biochemical communication between the different types of cells. After a description of the different models available, this chapter will give some clues to define the best model(s) depending of the applications and, finally, will discuss of the advantages and the limitations of these types of cultures to study cutaneous innervation mechanisms.

Major Role for TRPV1 and InsP3R in PAR2-Elicited Inflammatory Mediator Production in Differentiated Human Keratinocytes

PAR2 activation in basal keratinocytes stimulates inflammation via the Ca2+-dependent production of mediators such as IL-1β, TNF-α, and TSLP. In this study, we investigated PAR2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR2-activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes and DhPKs. SLIGKV-evoked Ca2+ store depletion did not trigger the store-operated Ca2+ entry (i.e., SOCE) through ORAI1 in DhPKs compared with undifferentiated human primary keratinocytes. The inhibition of phospholipase C and the concomitant inhibition of TRPV1 and inositol triphosphate receptor in DhPKs abrogated the SLIGKV-evoked Ca2+ store depletion; NF-κB activity; and the production of inflammatory mediators such as IL-1β, TNF-α, and TSLP. Taken together, these results indicate a key role for both InsP3R and TRPV1 in Ca2+ internal stores in the PAR2-evoked Ca2+ release and consequent skin inflammation in DhPKs. These findings may provide clues to understanding the pathological role of DhPKs in skin disorders in which PAR2 is known to be involved, such as atopic dermatitis, Netherton syndrome, and psoriasis.

A new tool to test active ingredient using lactic acid in vitro, a help to understand cellular mechanism involved in stinging test: An example using a bacterial polysaccharide (Fucogel®)

The stinging test is an in vivo protocol that evaluates sensitive skin using lactic acid (LA). A soothing sensation of cosmetics or ingredients can be also appreciated through a decrease in stinging score. To predict the soothing sensation of a product before in vivo testing, we developed a model based on an LA test and substance P (SP) release using a co‐culture of human keratinocytes and NGF‐differentiated PC12 cells. A bacterial fucose‐rich polysaccharide present in Fucogel® was evaluated as the soothing molecule in the in vivo stinging test and our in vitro model. Excluding toxic concentrations, the release of SP was significant from 0.2% of lactic acid for the PC12 cells and from 0.1% of lactic acid for the keratinocytes. When the pH was adjusted to approximately 7.4, LA did not provoke SP release. At these concentrations of LA, 0.1% of polysaccharide showed a significant decrease in SP release from the two cellular types and in co‐cultures without modifying the pH of the medium. In vivo, a stinging test using the polysaccharide showed a 30% decrease in prickling intensity vs the placebo in 19 women between the ages of 21 and 69. Our in vitro model is ethically interesting and is adapted for cosmetic ingredients screening because it does not use animal experimentation and limits human volunteers. Moreover, Fucogel® reduced prickling sensation as revealed by the in vivo stinging test and inhibits the neurogenic inflammation as showed by our new in vitro stinging test based on SP release.

Recherche de méthanol positive après l’administration d’esmolol en réanimation : à propos d’un cas

Nous rapportons le cas d’un patient âge de 60 ans, hospitalise au CHRU de Brest en raison de la decouverte fortuite de deux tumeurs hepatiques neuroendocrines de grade 2 d’origine intestinale. Ses antecedents medicaux comportaient une fibrillation auriculaire permanente bien toleree depuis 2009, necessitant un traitement par antiagregant plaquettaire seul (Kardegic®- acetylsalicylate de lysine). Admis au service de reanimation le 2 mars 2016 dans les suites d’une hepatectomie [...]