Project description:Lung interstitial macrophages (IMs) inhabit the lung parenchyma and are thought to contribute to lung immunoregulation and homeostasis. While recent progress has been made about the development, diversity and transcriptional regulation of lung IMs, the microenvironmental signals responsible for their tissue-specific identity remain unidentified. Here we found, in mice, that lung endothelial cell-derived Tgf 1 specifically triggered a core Tgf receptor-dependent lung IM signature in bone marrow-derived monocytes and macrophages (Macs). In vivo, myeloid-specific ablation of Tgf receptor signaling severely impaired monocyte-to-IM development, resulting in the accumulation of perivascular monocytes, decreased IM numbers and a severe loss of IM-intrinsic identity. Of note, monocyte-to-IM development was similarly impaired in the absence of endothelial-specific Tgf 1. Functionally, mice selectively lacking Tgf receptor in IMs exhibited a severe impairment of the lung immunoregulatory environment and prematurely developed lung hyperinflation, increased compliance and decreased elastance, changes classically associated with ageing. Our work identifies a novel endothelial - IM axis involving Tgf 1-Tgf r interactions that shapes IM identity and thereby sustains lung tissue integrity, thus providing foundations for IM-targeted interventions in the context of lung ageing and other chronic inflammatory disorders.
Project description:In this study we demonstrate that the lung mononuclear phagocyte system comprises three interstitial macrophages (IMs), as well as alveolar macrophages (AMs), dendritic cells and few extravascular monocytes. Through cell sorting and RNAseq analysis we were able to identify transcriptional similarities and differences between the three pulmonary IM subtypes, with reference to the more well-characterized alveolar macrophage
Project description:This experiment was performed to examine transcriptional differences between differentiated (Tim3+) and stem-like (CXCR5+) WT vs. Tgfbr2 KO antigen-specific CD8 cells.
Project description:This experiment was performed to examine transcriptional differences between differentiated (Tim3+) and stem-like (CXCR5+) WT vs. Tgfbr2 KO antigen-specific CD8 cells at day 30 after LCMV clone 13 infection.
Project description:This experiment was performed to examine transcriptional differences between WT and Tgfbr2 KO antigen-specific CD8 cells activated in established chronic infection.
Project description:Schistosomiasis, a prevalent cause of pulmonary hypertension (PH) globally, triggers type 2 inflammation, with interstitial macrophages (IMs) derived from monocytes playing a crucial role. These IMs produce thrombospondin-1 (TSP-1), activating TGF-β and driving PH pathology. Two distinct IM subpopulations were identified: resident FOLR2+ IMs expressing monocyte recruitment factors, and recruited CCR2+ IMs expressing TSP-1. Upon exposure to Schistosoma, the CCR2+ subpopulation expanded. Flow cytometry and single-cell RNA sequencing confirmed these findings, revealing crosstalk between IM subpopulations. The resident FOLR2+ IMs increased expression of monocyte recruitment ligands, while the recruited CCR2+ IMs expressed elevated TSP-1, activating TGF-β and contributing to PH. This study provides insights into the complex interplay of IM subpopulations in Schistosoma-induced PH, shedding light on potential therapeutic targets for this global health concern.