A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins

Chaudhary, Neha; Jayaraman, Archana; Reinhardt, Carsten; Campbell, Joshua D.; Bosmann, Markus

doi:10.1038/s41385-022-00534-7

Cited by 27 publications

(27 citation statements)

References 59 publications

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“…For example, C3 expression by synovial fibroblasts has been linked to inflammation-mediated tissue priming in arthritis 28 . Furthermore, analogous to what we have shown here for IM muscle, different complement genes are differentially expressed by different cells of the lung 29 . Specifically, lung macrophages express C1QA, C1QB, and C1QC, whereas lung mesothelial cells and fibroblasts expressed C1R, C1S, and C3 29 .…”

Section: Discussionsupporting

confidence: 87%

“…Furthermore, analogous to what we have shown here for IM muscle, different complement genes are differentially expressed by different cells of the lung 29 . Specifically, lung macrophages express C1QA, C1QB, and C1QC, whereas lung mesothelial cells and fibroblasts expressed C1R, C1S, and C3 29 . Taken together, these findings suggest that the coordinated local expression of complement genes is not specific to muscle tissue in IM but, rather, may be a general mechanism to regulate the complement pathway in inflamed tissues.…”

Section: Discussionsupporting

confidence: 87%

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Coordinated local RNA overexpression of complement induced by interferon gamma in myositis

Casal-Domínguez

Pinal‐Fernandez

Pak

et al. 2023

Sci Rep

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Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFNγ)-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFNγ-induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFNγ upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFNγ coordinates the local overexpression of complement genes that occurs in several cell types.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

Coordinated local RNA overexpression of complement induced by interferon gamma in myositis

Casal-Domínguez

Pinal‐Fernandez

Pak

et al. 2023

Sci Rep

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“…Moreover, although we have focused on FB in lung epithelial cells, other complement components have also been shown to modulate lung epithelial cell responses. For example, airway epithelial cells and alveolar (type 1 and type 2) epithelial cells also express C3aR, C5, C5aR1, and C5aR2, in addition to C3 and FB ( 22 , 56 , 57 ). C3aR activation on alveolar type 2 epithelial cells has recently been implicated in promoting endoplasmic reticulum stress and exacerbating bleomycin-induced lung injury, cellular apoptosis, and inflammation, which was suppressed by decay-accelerating factor (CD55) induction, a membrane-associated complement regulator ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the protective effects of C3 have largely been attributed to it being sourced from the liver and present in a high concentration in the circulation. However, we and others have previously demonstrated that C3 is also produced outside the liver by multiple immune and nonimmune cell populations (17)(18)(19)(20)(21)(22). This observation has implications, especially for organs that constantly interact with pathogens and environmental toxins, such as the lung (6,23).…”

Section: Introductionmentioning

confidence: 90%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

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“…In human lung, intracellular C3 protects airway epithelial cells from nutrient deprivation-induced cell death via a currently unknown mechanism 85 . C5 expression has also been observed in healthy human and mouse type II alveolar epithelial cells; however, its functional relevance has not yet been explored 86 . In bladder epithelial cells, the processed CYT-2 domain of CD46 controls hypoxia-inducible factor 1α (HIF1α) and is associated with malignant transformation and bladder cancer, probably via hyperactivation of MYC-mediated cell proliferation 45 .…”

Section: Non-immune Cells and Tissuesmentioning

confidence: 99%

Complosome — the intracellular complement system

West

Kemper

2023

Nat Rev Nephrol

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The complement system is a recognized pillar of host defence against infection and noxious self-derived antigens. Complement is traditionally known as a serum-effective system, whereby the liver expresses and secretes most complement components, which participate in the detection of bloodborne pathogens and drive an inflammatory reaction to safely remove the microbial or antigenic threat. However, perturbations in normal complement function can cause severe disease and, for reasons that are currently not fully understood, the kidney is particularly vulnerable to dysregulated complement activity. Novel insights into complement biology have identified cell-autonomous and intracellularly active complement -the complosome -as an unexpected central orchestrator of normal cell physiology. For example, the complo some controls mitochondrial activity, glycolysis, oxidative phosphorylation, cell survival and gene regulation in innate and adaptive immune cells, and in non-immune cells, such as fibroblasts and endothelial and epithelial cells. These unanticipated complosome contributions to basic cell physiological pathways make it a novel and central player in the control of cell homeostasis and effector responses. This discovery, together with the realization that an increasing number of human diseases involve complement perturbations, has renewed interest in the complement system and its therapeutic targeting. Here, we summarize the current knowledge about the complosome across healthy cells and tissues, highlight contributions from dysregulated complosome activities to human disease and discuss potential therapeutic implications. Nature Reviews Nephrology Review articlecontributions of the complosome to human disease, including kidney disease. Finally, we consider the therapeutic potential of targeting the complosome in complement-mediated pathologies and highlight key limitations and caveats of complosome-focused clinical approaches. Classical functions of systemic and local extracellular complementThe human complement system comprises >50 proteins that either circulate in blood (specifically, core components and some complement regulators) or lymph, or exist as cell membrane-bound proteins (regulators and receptors) 1,2 . C3 and C5 are major effector molecules that are mostly secreted by the liver in a pro-enzymatic form. Complement C3 and C5 activation is initiated when one or several activation pathways is triggered by pathogen-or damage-associated molecular patterns (Fig. 1a). This recognition leads to the formation of C3 and C5 convertases, which then cleavage-activate C3 into C3a and C3b, and C5 into C5a and C5b, respectively. C5b combines with serum C6-C9 to form the membrane attack complex (MAC), which induces direct lytic killing of pathogens or noxious target cells. C3b opsonizes microbes and noxious host cells, which induces scavenger cells to phagocytose and destroy C3b-tagged targets 1,2,15,16 . Receptors for the anaphylatoxins C3a and C5a -C3a receptor (C3aR) and C5aR1 and 2, respectively -are expressed b...

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A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins

Cited by 27 publications

References 59 publications

Coordinated local RNA overexpression of complement induced by interferon gamma in myositis

Coordinated local RNA overexpression of complement induced by interferon gamma in myositis

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Complosome — the intracellular complement system

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