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

• Published in: Infection and immunity Vol. 86; no. 12
• Main Authors: Govender, Melissa, Hurdayal, Ramona, Martinez-Salazar, Berenice, Gqada, Kaya, Pillay, Shandre, Gcanga, Lorna, Passelli, Katiuska, Nieuwenhuizen, Natalie E, Tacchini-Cottier, Fabienne, Guler, Reto, Brombacher, Frank
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2018
• Subjects: Animals; Autocrine Communication - immunology; CD4-Positive T-Lymphocytes; Cellular Microbiology: Pathogen-Host Cell Molecular Interactions; Disease Susceptibility - immunology; Disease Susceptibility - parasitology; Female; Gene Deletion; Interleukin-13 - immunology; Interleukin-4 Receptor alpha Subunit - genetics; Keratinocytes - immunology; Keratinocytes - parasitology; Leishmania major - immunology; Leishmaniasis, Cutaneous - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Paracrine Communication - immunology; Signal Transduction - immunology; Th2 Cells - immunology; skin; keratinocytes; IL-4 receptor alpha signaling; Leishmania major
• ISSN: 0019-9567; 1098-5522; 1098-5522
• DOI: 10.1128/IAI.00710-18

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 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 (KRT14 IL-4Rα ) mice on a BALB/c genetic background were generated by gene targeting and site-specific recombination (Cre/ ) under the control of the keratinocyte-specific locus. Following high-dose infection with 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 KRT14 IL-4Rα and littermate control IL-4Rα BALB/c mice. An intradermal infection with low-dose IL-81 and LV39 promastigotes in the ear showed results in infected KRT14 IL-4Rα BALB/c mice similar to those of littermate control IL-4Rα 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 infection.