Microbiota-dependent IGF-1 limits alveolar macrophage inflammatory function 2257596
TL;DR
It is found that IGF1R deficiency in AECs largely recapitulates AM phenotypes overserved in germ-free mice, with increased phagocytic capacity and enhanced inflammatory cytokine production in response to microbial stimuli.
Abstract
The impact of the systemic commensal microbiome on the lung microenvironment and alveolar macrophage (AM) polarization is largely unexplored. We find that AMs from mice lacking commensal microbiota (germ-fee) have heightened inflammatory function and that this is coincident with a reduction in IGF-1 protein in the germ-free lungs. The IGF-1 receptor gene (Igf1r) is highly expressed in alveolar epithelial cells (AECs), which are critical for mediating AM anti-inflammatory programming. To define how microbe-dependent IGF-1 shapes AM function, we generated two lines of conditional knockout mice that are Igf1rfl/fl, and with either LysMCre for the conditional deletion in myeloid cells, or Nkx2.1Cre for the conditional deletion in AECs. For both steady-state and after LPS stimulation, AMs from these mice were phenotypically evaluated by flow cytometry and assessed for functional capability such as cytokine secretion and phagocytosis. We also performed RNAseq analysis of AMs isolated from Igf1r deficient mice and germ-free mice. We find that IGF1R deficiency in AECs largely recapitulates AM phenotypes overserved in germ-free mice, with increased phagocytic capacity and enhanced inflammatory cytokine production in response to microbial stimuli. RNAseq analysis of germ-free AMs revealed 1639 differentially expressed genes, and protein interaction networks allowed us to identify a microbiota-dependent subnetwork of transcription factors including CEBPβ, PU.1, and Smad3. We are analyzing RNAseq from Igf1r deficient mice to identify AM programs regulated by IGF-1-dependent transcription factors. Next steps include spatial transcriptomics analysis of lungs from conditional Igf1r knockout mice to interrogate IGF-1 dependent AM-AEC crosstalk via ligand-receptor analysis and gene regulatory networks. This work will determine how microbiota-dependent IGF-1 stabilizes cell-cell communication to support lung homeostasis and regulate inflammation. n/a Mucosal and Regional Immunology (MUC)