ABSTRACT
Type 2 innate lymphoid cells (ILC2 cells) participate in host defense against helminth parasites and in allergic inflammation. Given their functional relatedness to type 2 helper T cells (T(H)2 cells), we explored whether Gfi1 acts as a shared transcriptional determinant in ILC2 cells. Gfi1 promoted the development of ILC2 cells and controlled their responsiveness during infection with Nippostrongylus brasiliensis and protease allergen-induced lung inflammation. Gfi1 'preferentially' regulated the responsiveness of ILC2 cells to interleukin 33 (IL-33) by directly activating Il1rl1, which encodes the IL-33 receptor (ST2). Loss of Gfi1 in activated ILC2 cells resulted in impaired expression of the transcription factor GATA-3 and a dysregulated genome-wide effector state characterized by coexpression of IL-13 and IL-17. Our findings establish Gfi1 as a shared determinant that reciprocally regulates the type 2 and IL-17 effector states in cells of the innate and adaptive immune systems.
Subject(s)
DNA-Binding Proteins/immunology , Immunity, Innate/immunology , Th2 Cells/immunology , Transcription Factors/immunology , Transcriptome/immunology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Flow Cytometry , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/immunology , GATA3 Transcription Factor/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Interleukin-1 Receptor-Like 1 Protein , Interleukin-13/genetics , Interleukin-13/immunology , Interleukin-13/metabolism , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Interleukin-33 , Interleukins/pharmacology , Lung/immunology , Lung/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mice , Mice, Inbred Strains , Mice, Knockout , Mice, Transgenic , Nippostrongylus/immunology , Nippostrongylus/physiology , Oligonucleotide Array Sequence Analysis , Receptors, Interleukin/genetics , Receptors, Interleukin/immunology , Receptors, Interleukin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Strongylida Infections/immunology , Strongylida Infections/parasitology , Th2 Cells/metabolism , Th2 Cells/parasitology , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptome/geneticsABSTRACT
Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.