Regulation of Pulmonary Bacterial Immunity by Follistatin-Like Protein 1

Abstract

Klebsiella pneumoniae is a common cause of antibiotic-resistant pneumonia. Follistatin-like protein 1 (FSTL-1) is highly expressed in the lung and is critical for lung homeostasis. The role of FSTL-1 in immunity to bacterial pneumonia is unknown. Wild-type (WT) and FSTL-1 hypomorphic (Hypo) mice were infected with Klebsiella pneumoniae to determine infectious burden, immune cell abundance, and cytokine production. FSTL-1 Hypo/TCRδ^-/- and FSTL-1 Hypo/IL17ra^-/- were also generated to assess the role of γδT17 cells in this model. FSTL-1 Hypo mice had reduced K. pneumoniae lung burden compared with that of WT controls. FSTL-1 Hypo mice had increased Il17a/interleukin-17A (IL-17A) and IL-17-dependent cytokine expression. FSTL-1 Hypo lungs also had increased IL-17A⁺ and TCRγδ⁺ cells. FSTL-1 Hypo/TCRδ^-/- displayed a lung burden similar to that of FSTL-1 Hypo and reduced lung burden compared with the TCRδ^-/- controls. However, FSTL-1 Hypo/TCRδ^-/- mice had greater bacterial dissemination than FSTL-1 Hypo mice, suggesting that gamma delta T (γδT) cells are dispensable for FSTL-1 Hypo control of pulmonary infection but are required for dissemination control. Confusing these observations, FSTL-1 Hypo/TCRδ^-/- lungs had an increased percentage of IL-17A-producing cells compared with that of TCRδ^-/- mice. Removal of IL-17A signaling in the FSTL-1 Hypo mouse resulted in an increased lung burden. These findings identify a novel role for FSTL-1 in innate lung immunity to bacterial infection, suggesting that FSTL-1 influences type-17 pulmonary bacterial immunity.

Keywords: Klebsiella pneumoniae; follistatin-like 1; interleukin-17; pneumonia.