title: Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin.
abstract: Human papillomaviruses (HPVs) have evoked numerous mechanisms to subvert host innate immunity and establish a local immunosuppressive environment to facilitate persistent virus infection. Topical application of 2,4-dinitrochlorobenzene (DNCB) was speculated to overcome this immunosuppressive environment and was employed in the immunotherapy of HPV-associated lesions. We have previously shown that DNCB treatment of skin expressing HPV16.E7 protein, the major oncogenic protein expressed in HPV-associated premalignant cervical epithelium, results in a hyperinflammatory response, with an associated induction of Th2 cytokines and infiltration of myeloid cells producing arginase-1, which also contributes to the hyperinflammation. However, the molecular mechanisms underlying arginase-1 induction and arginase-mediated hyperinflammation in K14.E7 skin have not been elucidated. Here, we show that HPV16.E7 protein expression as a transgene in skin is associated with enhanced IL-17A production by macrophages exposed to DNCB. Interestingly, induction of arginase-1 by DNCB is not seen in K14.E7 animals unable to express IL-17A. Further, blockade of either IL-17A or arginase activity alleviates DNCB-induced hyperinflammation through reduced recruitment of neutrophils, as a consequence of decreased CXCL1 and CXCL5 chemokine production. Thus, our findings suggest that increased IL-17A expression by macrophages in E7-expressing skin exposed to DNCB promotes arginase-1 induction and contributes directly to the observed hyperinflammation.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Qld., Australia.
authors.forename: Le Son
authors.initials: le S
authors.lastname: Tran
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004137:Dinitrochlorobenzene / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D004137:Dinitrochlorobenzene; C098680:Il17a protein, mouse; D020381:Interleukin-17; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C544448:Arg1 protein, mouse; D001119:Arginase