A role for the terminal C5-C9 complement pathway in idiopathic pulmonary fibrosis

Sikkeland, Liv Ingunn Bjoner; Ueland, Thor; Lund, May Brit; Durheim, Michael T.; Mollnes, Tom Eirik

doi:10.3389/fmed.2023.1236495

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…Albeit a low-resolution clustering analysis, we identified three macrophage (alveolar macrophages, Trem2 + , and Mertk + ), as well as transcriptionally distinct populations of monocytes (classical - Itgam/cd11b , Cx3cr1 ; inflammatory - Ccr2, Ly6c, Lyz2 ) ( 69 ). Our findings that complement signaling is involved in SP-C I73T injury and fibrosis is consistent with evidence that soluble defense collagens support activation, proliferation, and tissue-repair functions of macrophages ( 70 – 72 ). Alongside these signals, our results define inflammatory monocytes and monocyte-derived moieties (interstitial macrophages) as centrally involved in fibronectin/FN1 and osteopontin/SPP1 signaling in the fibrosing lung, a finding consistent with bleomycin-induced injury ( 42 , 73 – 78 ).…”

Section: Discussionsupporting

confidence: 89%

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis

Moos,

Cheminant,

Cowman

et al. 2024

Front. Immunol.

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IntroductionGenetic mutations in critical nodes of pulmonary epithelial function are linked to the pathogenesis of pulmonary fibrosis (PF) and other interstitial lung diseases. The slow progression of these pathologies is often intermitted and accelerated by acute exacerbations, complex non-resolving cycles of inflammation and parenchymal damage, resulting in lung function decline and death. Excess monocyte mobilization during the initial phase of an acute exacerbation, and their long-term persistence in the lung, is linked to poor disease outcome.MethodsThe present work leverages a clinical idiopathic PF dataset and a murine model of acute inflammatory exacerbations triggered by mutation in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene to spatially and phenotypically define monocyte/macrophage changes in the fibrosing lung.ResultsSP-C mutation triggered heterogeneous CD68+ macrophage activation, with highly active peri-injured cells relative to those sampled from fully remodeled and healthy regions. Ingenuity pathway analysis of sorted CD11b-SigF+CD11c+ alveolar macrophages defined asynchronous activation of extracellular matrix re-organization, cellular mobilization, and Apolipoprotein E (Apoe) signaling in the fibrosing lung. Cell-cell communication analysis of single cell sequencing datasets predicted pro-fibrogenic signaling (fibronectin/Fn1, osteopontin/Spp1, and Tgfb1) emanating from Trem2/TREM2+ interstitial macrophages. These cells also produced a distinct lipid signature from alveolar macrophages and monocytes, characterized by Apoe expression. Mono- and di-allelic genetic deletion of ApoE in SP-C mutant mice had limited impact on inflammation and mortality up to 42 day after injury.DiscussionTogether, these results provide a detailed spatio-temporal picture of resident, interstitial, and monocyte-derived macrophages during SP-C induced inflammatory exacerbations and end-stage clinical PF, and propose ApoE as a biomarker to identify activated macrophages involved in tissue remodeling.

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Section: Discussionsupporting

confidence: 89%

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis

Moos,

Cheminant,

Cowman

et al. 2024

Front. Immunol.

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“…Mechanistic studies into the role of secreted IgM in lung remodeling validated this protective role, showing an enrichment of extracellular matrix gene expression in the absence of IgM, and also point toward a role for complement as these related pathways were universally down-regulated in the absence of IgM. Terminal complement components have also been recently shown to be upregulated in BAL and plasma from patients with IPF 42 . What role this plays in disease pathogenesis remains to be determined.…”

Section: Discussionmentioning

confidence: 84%

A protective role for B-1 cells and oxidation-specific epitope IgM in lung fibrosis

Sturek,

Hannan,

Upadhye

et al. 2024

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a morbid fibrotic lung disease with limited treatment options. The pathophysiology of IPF remains poorly understood, and elucidation of the cellular and molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. B-1 cells are an innate B cell population which play an important role linking innate and adaptive immunity. B-1 cells spontaneously secrete natural IgM and prevent inflammation in several disease states. One class of these IgM recognize oxidation-specific epitopes (OSE), which have been shown to be generated in lung injury and to promote fibrosis. A main B-1 cell reservoir is the pleural space, adjacent to the typical distribution of fibrosis in IPF. In this study, we demonstrate that B-1 cells are recruited to the lung during injury where they secrete IgM to OSE (IgMOSE). We also show that the pleural B-1 cell reservoir responds to lung injury through regulation of the chemokine receptor CXCR4. Mechanistically we show that the transcription factor Id3 is a novel negative regulator of CXCR4 expression. Using mice with B-cell specific Id3 deficiency, a model of increased B-1b cells, we demonstrate decreased bleomycin-induced fibrosis compared to littermate controls. Furthermore, we show that mice deficient in secretory IgM (sIgM-/-) have higher mortality in response to bleomycin-induced lung injury, which is partially mitigated through airway delivery of the IgMOSE E06. Additionally, we provide insight into potential mechanisms of IgM in attenuation of fibrosis through RNA sequencing and pathway analysis, highlighting complement activation and extracellular matrix deposition as key differentially regulated pathways.

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“…Complement proteins can also be analyzed in bronchoalveolar lavage ( 34 ), cerebrospinal ( 35 ) or synovial fluids ( 36 ) as well as tears and aqueous/vitreous humor ( 37 ) which may better reflect a local complement activation.…”

Section: Introductionmentioning

confidence: 99%

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

Kirschfink,

Frazer-Abel,

Balogh

et al. 2024

Front. Immunol.

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IntroductionThe complement external quality assurance (EQA) program was first organized in 2010 by a group of researchers working in diagnostic complement laboratories. Starting in 2016, INSTAND e.V., a German, non-profit interdisciplinary scientific medical society dedicated to providing expert EQA programs for medical laboratories, started organizing the EQAs for complement diagnostic laboratories together with the same group of experienced scientists and doctors who also work as EQA experts. The aim of the current work is to provide descriptive analysis of the past seven years’ complement EQA results and evaluate timeline changes in proficiency testing.MethodsEach year, in March and October, blinded samples (normal, pathological) were sent to the participating diagnostic laboratories, where complement parameters were evaluated exactly as in daily routine samples. Since no reference method/target values exist for these parameters, and participants used different units for measurement, the reported results were compared to the stable mean (Algorithm A) of the participants using the same method/measurement units. A reported result was qualified as “passed” if it fell into the 30-50% evaluation/target range around the mean of reported results (depending on the given parameter).ResultsWhile the number of participating laboratories has increased in the past years (from around 120 to 347), the number of complement laboratories providing multiple determinations remained mostly unchanged (around 30 worldwide). C3, C4, C1-inhibitor antigen and activity determinations provided the best proficiency results, with >90% passing quotas in the past years, independent of the applied method. Determination of the functional activity of the three activation pathways was good in general, but results showed large variance, especially with the pathological samples. Complement factor C1q and regulators FH and FI are determined by only a few laboratories, with variable outcomes (in general in the 85-90% pass range). Activation products sC5b-9 and Bb were determined in 30 and 10 laboratories, respectively, with typical passing quotas in the 70-90% range, without a clear tendency over the past years.ConclusionWith these accumulated data from the past seven years, it is now possible to assess sample-, method-, and evaluation related aspects to further improve proficiency testing and protocolize diagnostic complement determinations.

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A role for the terminal C5-C9 complement pathway in idiopathic pulmonary fibrosis

Cited by 5 publications

References 21 publications

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis

A protective role for B-1 cells and oxidation-specific epitope IgM in lung fibrosis

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

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