Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA-mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.

Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects.

BACKGROUND: Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. AIM: Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. METHODS: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. RESULTS: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI. CONCLUSION: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.