Single-nucleus RNA sequencing of ex vivo precision-cut lung slices from normal human lung tissue
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE309373 | GEO | 2025/11/03
REPOSITORIES: GEO
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Project description:CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naive B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, in which there is a massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74, however, the function of this receptor in this environment was not fully characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells )tol-DCs( were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, conditionally CD74 -/- Cre-flox mice lacking CD74 in CD23+ mature B cells and mice lacking CD74 in the CD11c+ population and a CD74 inhibitor (DRQ), revealed that MIF secreted from the tumor cells activate CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the upregulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the downregulation of its transcription. The reduced levels of IL-1β lead to decreased anti-tumor activity by allowing expansion of the tol-DC, which induce the expansion of the Breg population, suggesting the cross-talk between these two populations. Taken together, these results suggest that CD74+ CD11c+ DCs are the dominant cell type involved in the regulation of the TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in triple-negative breast cancer.
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Project description:High expression alleles of the innate cytokine, macrophage migration inhibitory factor (MIF), are associated with the development or the severity of autoimmune inflammatory diseases, including rheumatoid arthritis. Numerous studies support MIF’s role in activating inflammatory pathways and MIF inhibition reduces joint pathology in different experimental models of arthritis. We examined the impact of gene deletion of MIF or its cognate receptor CD74 in the T cell-dependent model of collagen-induced arthritis (CIA) and observed the complete absence of arthritis development, suggesting an unforeseen role for MIF/CD74 signaling in the development of arthritogenic T cells. While MIF has been shown in model systems to contribute to T cell activation by augmenting innate responses, fewer than 1% of T lineage cells express CD74 in naïve spleens and lymph nodes, and its functional consequences in pathogenic T cell subpopulations have not been studied. We found CD74+ T cells to expand during CIA and to increase in number within joint synovium, where they express an effector memory phenotype and recapitulate CIA development upon transfer into naïve mice. We further found evidence for the presence of CD74+ T cells in the circulation and joint synovium of patients with rheumatoid arthritis. MIF-dependent, CD74+ T cells may contribute to the chronicity of rheumatoid synovitis and to disease relapse in previously inflamed joints.
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Project description:CD74, a Type II membrane glycoprotein and MHC class II chaperone (Ii), is normally expressed by cells associated with the immune system. CD74 also forms heterodimers with CD44 to generate receptors to macrophage migration inhibitory factor (MIF), a proinflammatory cytokine. Following targeted Cre-mediated deletion of Ikkβ in IkkβDeltaHep mice (a strain highly susceptible to chemically-induced hepatotoxicity and hepatocarcinogenesis), CD74 is abundantly expressed by hepatocytes throughout liver acini (as detected by specific Western blots and immunohistochemical stains); it is not observed in either control IkkβF/F hepatocytes or embryonic fibroblasts from Ikkβ-/- mice. Constitutive CD74 expression in IkkβDeltaHep hepatocytes is also accompanied by significantly augmented expression of CD44 and genes associated with antigen processing and host defense. These observations suggest that IkkβDeltaHep hepatocytes might directly respond to MIF signaling, accounting partly for the enhanced susceptibility of IkkβDeltaHep mice to hepatotoxins and hepatocarcinogens, and also might exhibit unusual immunological properties including antigen presentation. Total RNA samples were obtained from four 6-8 week-old male mice. The four RNA samples were processed as described in the PROTOCOLS section below.
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Project description:Background & Aims: Spatial location of steatosis is closely related to the progression of metabolic dysfunction-associated steatohepatitis (MASH), and reports suggest lipid-associated macrophages (LAMs) facilitate this progression. However, the underling mechanisms remain elusive. Approach & Results: Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in the hepatic periportal (PP) zone of MASH mice, suggesting a vital role of PP zone in the MASH progression. Thrsp (Spot14), involved in fatty acid synthesis, was markedly elevated in the livers of MASH patients and mice. Notably, CellPhoneDB analysis identified strong interactions between Cd74 and macrophage migration inhibitory factor (MIF) within Thrsp-high zone. Furthermore, Thrsp, Cd74, Mif, Col3a1 and LAMs markers were prominently co-localized in hepatic PP zone of MASH mice, suggesting Thrsp-mediated crosstalk in this region played crucial role in MASH progression. Hepatic Thrsp overexpression/knockout experiments confirmed that Thrsp drove MASH progression by recruiting Cd74+ LAMs mediated by MIF. Mechanistically, Thrsp promoted hepatic palmitic acid (PA) synthesis, mainly by promoting hepatic de novo lipogenesis, and disturbing the binding of FASN-TRIM21, thereby inhibiting FASN’s ubiquitination. Cd74+ LAMs were activated and recruited by chemokine-like MIF secreted from hepatocytes and macrophages stimulated with PA. Additionally, the compound C6 identified as a Thrsp inhibitor, significantly ameliorated MASH in mice. Conclusions: Our study demonstrates that Thrsp drives MASH progression by recruiting Cd74+ LAMs mediated by MIF in hepatic PP zone, providing novel insights into the spatial zonation and crosstalk between lipogenic hepatocytes and LAMs that may result in novel therapies for MASH.
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Project description:CD74 (invariant chain), expressed on B cells, is directly involved in shaping the B cell repertoire by regulating their survival in health and disease. Binding of its ligand, macrophage migration inhibitory factor (MIF), induces a cascade that results in CD74 intramembrane proteolysis, and the release of the CD74 intracellular domain (CD74-ICD). CD74-ICD translocates to the nucleus where it induces activation of transcription. In the current study, we characterize the transcription regulator activities of CD74 by analysing its ability to alter gene expression in mRNA levels.
2022-11-03 | GSE181675 | GEO