Cutaneous psoriasis improves with targeted pathway inhibition, but the homeostatic mechanisms that normally restrain chronic tissue inflammation remain incompletely understood. We single-cell profiled human psoriatic and normal skin resident memory T cell transcriptomes to reveal a gradated transcriptional program of coordinately regulated inflammation-suppressive genes. This program, which is sharply suppressed in psoriatic lesional skin, strikingly restricts Th17 cytokine and other inflammatory mediators on the single-cell level. We have recently shown CRISPR-based deactivation of core components of this inflammation-suppressive program replicates the elevated IL17F, IL26, and IFNG in psoriatic memory T cells deficient in these transcripts, functionally validating their influence. Combinatoric expression analysis establishes a dominant single-cell trajectory of increasingly inflamed psoriatic resident memory T cells but can also distinguish the influence of individual suppressive program transcripts on specific inflammatory mediators. Finally, we find that therapeutic IL23 blockade reduces Th17 cell frequency in psoriatic skin but fails to re-establish expression of this inflammation-suppressive transcriptional program, illustrating how treated lesions may be primed for recurrence upon withdrawal of treatment.

BACKGROUND:Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part.METHODS:This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models.RESULTS:In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy.DISCUSSION:Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Human inflammation activates dynamically, but the mechanisms underlying such sensitive kinetics remain incompletely understood. We single-cell profiled transcriptomes and epitopes from 24 diverse rashes in adults, including psoriasis, atopic dermatitis, lichen planus, and bullous pemphigoid. The tristetraprolin family members ZFP36 and ZFP36L2 were identified as recurrently, highly repressed transcripts in T cells (logeFC = -0.47 and -0.85 respectively; adjPvals < 0.001). CRISPR-mediated knockdown of these genes induced a greater than 2-fold secretion of multiple inflammatory cytokines in T cells, including TNF-α (p = 0.008), GM-CSF (p = 0.002), IFNγ (p = 0.030), and IL13 (p = 0.044). Interestingly, cytokine induction was greatest preceding stimulation, suggesting tristetraprolins amplify signaling at the onset of inflammation. Supporting this temporal model, we also found that attenuation of ZFP36L2 mRNA precedes induction of cytokine transcripts in stimulated T cells. Collectively, our data implicate tristetraprolins as early, central regulators of inflammation in human skin and suggest an actionable point for therapeutic modulation.