Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo.

ABSTRACT:

Rationale

Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection.

Methods

We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA.

Results

Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic® prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis. The TGF-? family ligand activin A was upregulated ten-fold in infected skin. Topically-applied ALK5/TG?R1 signaling inhibitor synergized with vaccinia immune globulin (VIG) to promote vaccinia clearance and limit weight loss. In cultured keratinocytes, filaggrin-directed siRNA inhibited programmed necrosis and inflammatory cytokine release induced by ACAM-2000, while viral growth was increased.

Conclusions

Our findings may point to a novel role for filaggrin in early antiviral responses in skin. In wounded skin with underlying barrier defects, chronically elevated activin A levels may contribute to skin remodeling and cutaneous pathogen persistence. Inhibition of ALK5/TGF?R1 signaling may provide a novel co-therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia.

SUBMITTER: He Y 

PROVIDER: S-EPMC5231274 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature