The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms. We discuss IL-1 family cytokines in the context of IL-4/IL-13 and IL-23/IL-17 axis-driven diseases and highlight consequences of human loss/gain of function mutations in activating or inhibitory pathway molecules. This review highlights recent findings that emphasize the importance of IL-1 family cytokines in both physiological and pathological cutaneous inflammation and emergent translational therapeutics that are helping further elucidate these cytokines.

D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.

Correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds

Background Despite noticeable improvement in anti-malarial treatment, rapid growth of resistant malaria strains points out the need for continuous development of novel anti-malarials to fight the disastrous infection. Haemozoin is considered as a novel inhibitory pathway for new anti-malarial drugs, therefore, this study aimed to systematically review all articles investigating the correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds. Methods A literature search was conducted on 22 October 2017 in eight databases for relevant in vitro articles reporting the correlation between anti-malarial and anti-haemozoin of anti-malarial compounds, based on the constructed search terms and inclusion criteria. ToxRtool was used to assess quality of each study. Results A total of ten articles were included in the review. In vitro anti-malarial and anti-haemozoin activity had a good correlation for quinolines for sensitive strains (R2 ranging from 0.66 to 0.95) and xanthones (Spearman ρ = 0.886). However, these correlations were reached after removing some compounds which had non-detectable anti-malarial or anti-haemozoin effects. Other structures (acridines, pyrolidines) showed negligible correlation with Spearman ρ ranging from 0.095 to 0.381 for acridines, and r varying from 0.54 to 0.62 for pyrolidines. Some good correlations were only shown in a logarithmic manner or when the anti-malarial activity was normalized. Conclusion The results raised a relative relationship between anti-haemozoin and in vitro anti-malarial activities. Some studies reported compounds that were effective in the inhibition of haemozoin formation, but failed to inhibit the parasite survival and vice versa. The correlation results in these studies were calculated after these compounds were removed from their analysis. The ability of anti-malarial compounds to accumulate inside the reaction site might strengthen their anti-malarial activity.

The rostroventral part of the thalamic reticular nucleus modulates fear extinction

The thalamus has been implicated in fear extinction, yet the role of the thalamic reticular nucleus (TRN) in this process remains unclear. Here, in mice, we show that the rostroventral part of the TRN (TRNrv) is critically involved in the extinction of tone-dependent fear memory. Optogenetic excitation of TRNrv neurons during extinction learning dramatically facilitated, whereas the inhibition disrupted, the fear extinction. Single unit recordings demonstrated that TRNrv neurons selectively respond to conditioned stimuli but not to neutral stimuli. TRNrv neurons suppressed the spiking activity of the medial part of the dorsal midline thalamus (dMTm), and a blockade of this inhibitory pathway disrupted fear extinction. Finally, we found that the suppression of dMTm projections to the central amygdala promotes fear extinction, and TRNrv neurons have direct connections to this pathway. Our results uncover a previously unknown function of the TRN and delineate the neural circuit for thalamic control of fear memory.