# High-dimensional single-cell analyses reveal neutrophil heterogeneity in guttate psoriasis

## TL;DR

This study reveals diverse neutrophil types in guttate psoriasis skin, highlighting immature neutrophils that may contribute to disease development.

## Contribution

The study is the first to comprehensively profile neutrophil heterogeneity in guttate psoriasis using high-dimensional single-cell analyses.

## Key findings

- An immature neutrophil subset enriched in GP skin shows antigen processing and presentation features.
- GAS-induced neutrophils promote CD4+ T cell proliferation via HLA-DR.
- Other GP neutrophil subsets are linked to migration, extracellular trap formation, and phagocytosis.

## Abstract

Guttate psoriasis (GP) is associated with streptococcal throat infection. Neutrophils are the first immune cells to respond to Group A Streptococcal (GAS) infection, but detailed analysis of their contribution to GP pathogenesis is lacking. The study primarily focuses on phenotyping the neutrophils located at the site of inflammation in GP skin and understanding their specific contribution to the pathogenesis of the disease.

Here, we performed a comprehensive immunophenotypic and transcriptomic analysis of neutrophils from blood and inflamed GP skin using high-dimensional single-cell protein and RNA analyses. Ex vivo stimulation of neutrophils and co-culture with CD4+ T cells was performed to validate the function of neutrophil subsets upon GAS stimulation.

We uncovered high diversity of human neutrophils in GP, with enrichment of an immature subset in GP skin that exhibited antigen processing and presentation signature. A similar subset in healthy controls was observed only upon ex vivo stimulation of neutrophils with GAS bacteria. Additionally, the GAS-induced neutrophil subset was found to induce CD4+ T cell proliferation mediated by HLA-DR. Other neutrophil subsets that expanded in GP were characterised by enrichment of genes related to neutrophil migration, formation of neutrophil extracellular traps and phagocytosis.

Our study depicts the landscape of neutrophils in GP skin and highlights HLA-DR+ neutrophils with possible role in disease pathogenesis.

This work was supported by 10.13039/501100022654HudFonden, Psoriasisfonden, Gösta A Karlssons 60-års fond, Magnus Bergvall stiftelse, Åke Wibergs stiftelse, and 10.13039/501100004047Karolinska Institute. AP was supported by 10.13039/501100022654HudFonden. PA was partially supported by Karolinska Institute’s doctoral funding (KID). LPM was supported by grants from 10.13039/501100003748Svenska Sällskapet för Medicinsk Forskning (SSMF) and 10.13039/501100001704European Society of Clinical Microbiology and Infectious Diseases (ESCMID). UN was supported by grants from the 10.13039/501100004359Swedish Research Council. JL was supported by Region Stockholm (clinical postdoctoral appointment). ML was supported by the Swedish Childhood Cancer research fund and the 10.13039/501100004047Karolinska Institute. Part of the data handling was enabled by resources at project number SNIC-2021/22-49 provided by the Swedish National Infrastructure for Computing (SNIC), partially funded by the 10.13039/501100004359Swedish Research Council through grant agreement no. 2018-05973.