Deletion of Interleukin-4 Receptor Alpha-Responsive Keratinocytes in BALB/c Mice Does Not Alter Susceptibility to Cutaneous Leishmaniasis

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Abstract
The skin microenvironment at the site of infection plays a role in the early events that determine protective T helper 1/type 1 immune responses during cutaneous leishmaniasis (CL) infection. During CL in nonhealing BALB/c mice, early interleukin-4 (IL-4) can instruct dendritic cells for protective Th1 immunity. Additionally, keratinocytes, which are the principal cell type in the skin epidermis, have been shown to secrete IL-4 early after Leishmania major infection. Here, we investigated whether IL-4/IL-13 signaling via the common IL-4 receptor alpha chain (IL-4Rα) on keratinocytes contributes to susceptibility during experimental CL. To address this, keratinocyte-specific IL-4Rα-deficient (KRT14cre IL-4Rα−/lox) mice on a BALB/c genetic background were generated by gene targeting and site-specific recombination (Cre/loxP) under the control of the keratinocyte-specific krt14 locus. Following high-dose infection with L. major IL-81 and LV39 promastigotes subcutaneously in the footpad, footpad swelling, parasite burden, IFN-γ/IL-4/IL-13 cytokine production, and type 1 and type 2 antibody responses were similar between KRT14cre IL-4Rα−/lox and littermate control IL-4Rα−/lox BALB/c mice. An intradermal infection with low-dose L. major IL-81 and LV39 promastigotes in the ear showed results in infected KRT14cre IL-4Rα−/lox BALB/c mice similar to those of littermate control IL-4Rα−/lox BALB/c mice, with the exception of a significant decrease observed in parasite burden only at the site of LV39 infection in the ear. Collectively, our results show that autocrine and paracrine signaling of IL-4/IL-13 through the IL-4Rα chain on keratinocytes does not influence the establishment of a nonhealing Th2 immune response in BALB/c mice during L. major infection.
Funding Information
  • Swiss National Science Foundation (SNF) and South African National Research Foundation (IZLSZU3_14906)
  • Swiss National Science Foundation (3100030_166651/1)
  • South African National Research Foundation
  • South African Research Chair Initiative
  • Department of Science and Technology (DST) of South Africa and NRF for the Swiss-South African Joint Research Programme (UID 87399)
  • South African Medical Council
  • Department of Science and Technology (DST) of South Africa/South African National Research Foundation (NRF) Postgraduate Training Programme (UID 92532)
  • Wellcome Trust CIDRI-Africa (203135Z/16/Z)
  • Department of Science and Technology, Republic of South Africa

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