Biology subjects

Haub, J.

Publications and source records attributed to Haub, J..

3 recordsLinked to original sources

bioRxiv2025

Human chronic inflammation is orchestrated by spatially restricted inflammation-activated Dendritic cells

Dendritic cells (DCs) form coordinated networks that orchestrate inflammatory responses across tissues. Upon activation, conventional dendritic cells (DCs) undergo changes in their transcriptome, phenotype, and function, depending on the tissue microenvironment. The role of DC activation during human chronic inflammation has yet to be explored. To address this, we aimed to investigate activated DCs across a range of chronically inflamed human tissues, with a focus on cervical lymph nodes (LNs). We performed scRNAseq and flow cytometry on healthy, acutely, chronically inflamed, and cancer-associated human cervical (LNs) and identified a novel inflammation-associated DC (iaDC) cell state, found only within chronically inflamed LNs. iaDCs were defined by a unique cytokine expression profile (CXCL9, CXCL10, IL1B) and could be phenotypically distinguished from other activated DCs by their elevated expression of CD1C, CD206, CD319, and CD274. Functionally, we found that IFN{gamma} signaling induces DC2s to enter the iaDC cell state and that this process can be abrogated by inhibition of JAK-STAT signaling. Using spatial transcriptomics, we observed LN iaDC residing within a specific chronic inflammatory niche, which was enriched for inflammatory monocytes, NK cells, and effector memory CD4+ and CD8+ T cells. Extrapolating our findings to other chronic inflammation-associated diseases, we similarly observed the emergence of iaDCs within the intestines of treatment-resistant Crohns Disease patients, synovial membranes and lymph nodes of rheumatoid arthritis patients and lungs of sarcoidosis patients. Similarly to the lymph node, iaDCs were found to reside in conserved chronic inflammation-associated spatial niches within the small intestine of affected individuals and displayed equivalent transcriptional characteristics and surrounding cellular neighborhoods. Collectively, these data highlight a previously unexplored role of iaDCs in human chronic inflammatory diseases and propose a conserved spatially restricted iaDC-populated chronic inflammatory niche associated with resistance to therapy. These findings highlight novel avenues to shape inflammatory trajectories by targeting iaDCs and their spatial niches, for example, by inhibiting JAK-STAT signaling.

immunology↗

bioRxiv2023

Early-stage idiopathic pulmonary fibrosis is characterized by bronchoalveolar accumulation of SPP1+ macrophages

Patients affected by idiopathic pulmonary fibrosis (IPF), a progressive chronic and eventually fatal lung disease with unknown cause, suffer from delayed diagnosis and limited personalized treatment options due to the lack of predictive and staging relevant disease markers. Prior studies focused on the cellular and transcriptomic changes found in lung tissue during terminal IPF-associated lung fibrosis. In clinical routine, bronchoscopy is applied for diagnosis and staging of suspected IPF affected individuals, thus providing us with a clinically applicable window, to study the cellular and transcriptional changes within affected individuals at the time of diagnosis. Here we study a cohort consisting of 11 IPF affected individuals and 11 healthy controls. We investigate their single cell transcriptomic profile alongside the surface phenotype of alveolar-resident immune cells. Single cell transcriptional analysis reveals accumulation of SPP1+ macrophages (SPP1+M{varphi}) within the alveolar space during early stage diagnosed IPF, in the absence of a decline in lung function. SPP1+M{varphi} were characterized by high expression of lipid storage and handling genes, accumulation of intracellular cholesterol and expression of proinflammatory cytokine expression. In silico developmental trajectory analysis revealed that SPP1+M{varphi} are likely derived from classical monocytes. Finally, to confirm the clinical diagnostic value of SPP1+ M{varphi}, we developed a flow cytometry panel to rapidly identify and test for the presence of SPP1+ M{varphi} in bronchoalveolar lavage samples. The new panel has confirmed the increased frequency of SPP1+ M{varphi} in early-IPF in an independent validation cohort. Taken together, we show that SPP1+ M{varphi} are associated with early IPF pathogenesis in the absence of a decline in lung function, thus providing a clinically valuable markers for diagnosis of early IPF in clinical practice. HighlightsO_LIIPF patients can be stratified into early and advanced disease groups based on clinical features. C_LIO_LISingle cell transcriptomic and high dimensional flow cytometry enabled mapping of the myeloid compartment across the continuum of idiopathic pulmonary fibrosis associated disease states. C_LIO_LISPP1+M{varphi} accumulated during early clinical stage of IPF. C_LIO_LIDevelopment of a clinically applicable SPP1M{varphi} identification panel. C_LI

immunology↗

bioRxiv2022

Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms which lead to the functional and developmental adaptation of lung-associated macrophages remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal {beta}-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonal macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging and flow cytometric characterization paired to in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Dectin-1 - Card9 signaling-dependent monocyte-derived macrophages (MoAM). MoAMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic and produced large amounts of interleukin 6 upon restimulation. Myeloid cell specific ApoE ablation inhibited monocyte to MoAM differentiation dependent on M-CSF secretion, promoting MoAM cell death thus impeding MoAM maintenance. In vivo, {beta}-glucan-elicited MoAMs limited the bacterial burden of Legionella pneumophilia post infection and ameliorated fibrosis severity in a murine fibrosis model. Collectively these data identify MoAMs that are generated upon environmental cues and ApoE as an important determinant for lung immune resilience.

immunology↗