RAC1 activation drives pathologic interactions between the epidermis and immune cells
Mårten C.G. Winge, … , Elizabeth A. Waterman, M. Peter Marinkovich
Mårten C.G. Winge, … , Elizabeth A. Waterman, M. Peter Marinkovich
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2661-2677. https://doi.org/10.1172/JCI85738.
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Research Article Dermatology

RAC1 activation drives pathologic interactions between the epidermis and immune cells

Abstract

Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

Authors

Mårten C.G. Winge, Bungo Ohyama, Clara N. Dey, Lisa M. Boxer, Wei Li, Nazanin Ehsani-Chimeh, Allison K. Truong, Diane Wu, April W. Armstrong, Teruhiko Makino, Matthew Davidson, Daniela Starcevic, Andreas Kislat, Ngon T. Nguyen, Takashi Hashimoto, Bernard Homey, Paul A. Khavari, Maria Bradley, Elizabeth A. Waterman, M. Peter Marinkovich

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Figure 7

Epidermal RAC1 activation induces NFκB and immune-dependent STAT3 signaling.

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Epidermal RAC1 activation induces NFκB and immune-dependent STAT3 signal...
Expression of epidermal (A and B) p-STAT3, (C and D) p-RELA, and (A–D) COL7 and desmoglein 3 (DSG3), with representative inserts of Z-stacks of Rac1V12 and psoriasis. p-STAT3, p-RELA, red; COL7, DSG3, green; DNA, blue. (E) Western blot and (F and G) quantification of p-STAT3 and acetyl p65 (relative to β-actin) in Rac1V12 and WT skin. Reduced p-STAT3 (H) and CD3 (I) in NOD/SCID Rac1V12 mice lacking functional lymphocytes. p-STAT3, CD3, red; DNA, blue. Scale bars: 50 μm (A–D, H, and I), 10 μm (Z-stack inserts A–D). (A–D) n = 5 per condition; (E–G) n = 3 per condition; (H and I) n = 3 per condition. (F and G) *P < 0.05, by unpaired t test. Error bars represent SEM. RAC1, Rac1V12 mouse.