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.

Myeloid-Derived Suppressor Cells in Psoriasis Are an Expanded Population Exhibiting Diverse T-Cell–Suppressor Mechanisms

“…Secondly, in 4 patients, we found heterogeneity: MDSCs of some patients employed IL-17 and arginase I. In these cases, IL-17 may upregulate arginase I expression in MDSCs (He et al , 2010; Tran le et al , 2015). By contrast, MDSCs from other patients employed the IFN-γ/iNOS axis (Faure et al , 1999).…”

Obesity impairs resistance toLeishmania majorinfection in C57BL/6 mice

“…Moreover, IL-17KO C57BL/6 mice expressed lower levels of mRNA coding for molecules associated with M2 activity, including arginase 1 (54). Another study showed that IL-17A induces arginase 1 production in a model of human Papillomavirus (55). In this case, arginase 1 would be active in M2-macrophages.…”

Association of local immune suppression in skin with HPV-induced epithelial hyperplasia

“…E7 interaction with Rb protein is necessary to attract T cells to E7 transgenic skin K14.E7 transgenic mouse skin exhibits an immune cell infiltrate and regulatory cytokine production (Chandra et al, 2016;Choyce et al, 2013;Gosmann et al, 2014a;Gosmann et al, 2014b;Mattarollo et al, 2010b;Tran le et al, 2015). To determine whether the lymphocytic infiltrate observed in E7 transgenic skin requires interaction of E7 with Rb protein, we utilized a double transgenic mouse model expressing HPV16 E7 and a mutant Rb (K14.E7xRb L/L ) that fails to bind E7 and therefore lacks epithelial hyperplasia without perturbing other Rb functions (Balsitis et al, 2005;Dick et al, 2000).…”

“…Arg-1 production is independent of T and B lymphocytes, as evidenced by no significant difference in Arg-1 expression between K14.E7 and K14.E7xRag -/mice, where no T cells and B cells exist in the latter (Tran et al, 2014). Depletion of IL-17 abolished DNCB-induced Arg-1 production and hyper-inflammation, indicating that IL-17 is the key inducer of Arg-1 (Tran le et al, 2015). Taken together, local determinants, such as IL-1β, Arg-1 and IL-17, control the outcome of K14.E7 skin grafts and inflammatory response towards topical immune therapies.…”

“…and consequent recruitment of mast cells (Bergot et al, 2014), ii) increased expression of potent neutrophil chemoattractants including Cxcl1, Cxcl2 and Cxcl5 in DNCB-treated K14.E7 skin (Tran le et al, 2015), and iii) expression of Ccr6, the receptor for chemokine Ccl20, on CD4 + T cells in K14.E7 skin is higher than lymph node of K14.E7 (Choyce et al, 2013). Although we have explored the relationship between several chemokines and immunocyte recruitment in K14.E7 skin, the epithelial hyperplasia-directed, as well as the degree of contribution of the E7-Rb interaction to lymphocyte-recruiting signal have not yet been understood.…”