Abstract
Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor кB (NF-кB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-кB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-кB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.
| Original language | English |
|---|---|
| Article number | eabj0324 |
| Journal | Science Translational Medicine |
| Volume | 14 |
| Issue number | 630 |
| DOIs | |
| State | Published - Feb 2 2022 |
Funding
Acknowledgments: We thank M. Karin (UCSD) for providing transgenic mice. This research used resources of the Oak Ridge Leadership Computing Facility, which is a Department of Energy Office of Science User Facility supported under contract DE-AC05-00OR22725. Funding: This study was supported by NIH grants R01-DE019108 (to D.T.G.), K08-DE027129 (to K.I.K.), R01-DE030415 (to K.I.K.), R01-DA051908 (to D.J., M.R.G., and J.J.M.), R01-ES028114 (to J.T.S), and P30-AR069589 (to J.T.S.). M.L.H. and Y.H. are supported by T32-AR007465 (NIAMS), and M.L.H. is supported by the Waine C. Johnson Endowed Research Fellowship. Author contributions: Study concept and design: K.I.K., J.J.M., D.J., J.T.S., and D.T.G. In vivo mouse experiments: K.I.K., B.P.D., H.Z., E.H., and A.T.N. In vitro experiments with primary mouse and human fibroblasts: K.I.K. and M.L.H. RNAScope experiments: Y.H. and S.P. Data analysis: K.I.K, J.J.M., B.P.D., H.Z., Y.H., E.H., A.T.N., S.P., F.A., A.C., J.R., M.R.G., M.L.H., J.T.S., D.J., and D.T.G. scRNA-seq and bioinformatics analysis: K.I.K., J.J.M., A.C., J.R., M.R.G., D.J., and D.T.G. Supervision: D.J., J.T.S., and D.T.G. Funding acquisition: K.I.K., J.T.S., D.J., and D.T.G. Drafting of original manuscript: K.I.K., J.J.M., D.J., J.T.S., and D.T.G. Critical review and editing of draft: K.I.K., J.J.M., M.C.W., Y.C., S.E.M., A.C., J.R., J.T.S., D.J., and D.T.G. Competing interests: The authors declare that they have no competing interests. Data and materials availability. All data associated with this study are found in the main text and the Supplementary Materials. scRNA-seq data are available through Gene Expression Omnibus (GEO: GSE172226). Computer codes for scRNA-seq analyses are available at https://doi.org/10.5281/zenodo.5826191. Animals and human neonatal primary fibroblasts from this study can be made available via material transfer agreement upon request to the corresponding authors.