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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2661-2677 |
| Number of pages | 17 |
| Journal | Journal of Clinical Investigation |
| Volume | 126 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
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RAC1 activation drives pathologic interactions between the epidermis and immune cells. / Winge, Mårten C G; Ohyama, Bungo; Dey, Clara N.; Boxer, Lisa M.; Li, Wei; Ehsani-Chimeh, Nazanin; Truong, Allison K.; Wu, Diane; Armstrong, April W.; Makino, Teruhiko; Davidson, Matthew; Starcevic, Daniela; Kislat, Andreas; Nguyen, Ngon T.; Hashimoto, Takashi; Homey, Bernard; Khavari, Paul A.; Bradley, Maria; Waterman, Elizabeth A.; Marinkovich, M. Peter.
In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2661-2677.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - RAC1 activation drives pathologic interactions between the epidermis and immune cells
AU - Winge, Mårten C G
AU - Ohyama, Bungo
AU - Dey, Clara N.
AU - Boxer, Lisa M.
AU - Li, Wei
AU - Ehsani-Chimeh, Nazanin
AU - Truong, Allison K.
AU - Wu, Diane
AU - Armstrong, April W.
AU - Makino, Teruhiko
AU - Davidson, Matthew
AU - Starcevic, Daniela
AU - Kislat, Andreas
AU - Nguyen, Ngon T.
AU - Hashimoto, Takashi
AU - Homey, Bernard
AU - Khavari, Paul A.
AU - Bradley, Maria
AU - Waterman, Elizabeth A.
AU - Marinkovich, M. Peter
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978371859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978371859&partnerID=8YFLogxK
U2 - 10.1172/JCI85738
DO - 10.1172/JCI85738
M3 - Article
VL - 126
SP - 2661
EP - 2677
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 7
ER -