AUTHOR=Costa Sara , Bevilacqua Dalila , Caveggion Elena , Gasperini Sara , Zenaro Elena , Pettinella Francesca , Donini Marta , Dusi Stefano , Constantin Gabriela , Lonardi Silvia , Vermi William , De Sanctis Francesco , Ugel Stefano , Cestari Tiziana , Abram Clare L. , Lowell Clifford A. , Rodegher Pamela , Tagliaro Franco , Girolomoni Giampiero , Cassatella Marco A. , Scapini Patrizia TITLE=Neutrophils inhibit γδ T cell functions in the imiquimod-induced mouse model of psoriasis JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1049079 DOI=10.3389/fimmu.2022.1049079 ISSN=1664-3224 ABSTRACT=Background

Psoriasis is a chronic skin disease associated with deregulated interplays between immune cells and keratinocytes. Neutrophil accumulation in the skin is a histological feature that characterizes psoriasis. However, the role of neutrophils in psoriasis onset and development remains poorly understood.

Methods

In this study, we utilized the model of psoriasiform dermatitis, caused by the repeated topical application of an imiquimod containing cream, in neutrophil-depleted mice or in mice carrying impairment in neutrophil functions, including p47phox -/- mice (lacking a cytosolic subunit of the phagocyte nicotinamide adenine dinucleotide phosphate - NADPH - oxidase) and Sykfl/fl MRP8-cre+ mice (carrying the specific deletion of the Syk kinase in neutrophils only), to elucidate the specific contribution of neutrophils to psoriasis development.

Results

By analyzing disease development/progression in neutrophil-depleted mice, we now report that neutrophils act as negative modulators of disease propagation and exacerbation by inhibiting gammadelta T cell effector functions via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production. We also report that Syk functions as a crucial molecule in determining the outcome of neutrophil and γδ T cell interactions. Accordingly, we uncover that a selective impairment of Syk-dependent signaling in neutrophils is sufficient to reproduce the enhancement of skin inflammation and γδ T cell infiltration observed in neutrophil-depleted mice.

Conclusions

Overall, our findings add new insights into the specific contribution of neutrophils to disease progression in the IMQ-induced mouse model of psoriasis, namely as negative regulatory cells.