Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function.
Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17-induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105.
Sirish K
SK
Ippagunta
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Ruchika
R
Gangwar
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
David
D
Finkelstein
Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105.
Peter
P
Vogel
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Stephane
S
Pelletier
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Sebastien
S
Gingras
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105.
Vanessa
V
Redecke
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; hans.haecker@stjude.org.
Hans
H
Häcker
D000634:Aminoquinolines / Q000009:adverse effects; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D000077271:Imiquimod; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome
D000634:Aminoquinolines; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D053759:Interleukin-23; D000077271:Imiquimod
Abin1; IL-17; Tnip1; keratinocytes; psoriasis
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