Supplementary Material for: Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin

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.