Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium

Venosa, Alessandro; Cowman, Sophie J.; Katzen, Jeremy; Tomer, Yaniv; Armstrong, Brittnie S.; Mulugeta, Surafel; Beers, Michael F.

doi:10.3389/fimmu.2021.665818

Cited by 12 publications

(14 citation statements)

References 65 publications

(109 reference statements)

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“…Differential counting of BALF cytospins revealed no alterations in the distribution of monocytes, eosinophils, neutrophils, or lymphocytes ( Figure 4, C and D ). We also assessed immune populations in the lung parenchyma by flow cytometry analysis using a previously published protocol illustrated in Supplemental Figure 5 , A and C ( 34 , 37 , 38 ). When compared with Ptgfr +/+ controls, at D14, the induced I ER -Sftpc I73T /Ptgfr –/– cohort had similar levels of both myeloid and lymphocyte lineages ( Figure 4E and Supplemental Figure 5B ).…”

Section: Resultsmentioning

confidence: 99%

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Rodriguez,

Tang,

Roque Barboza

et al. 2023

JCI Insight

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Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F 2α , and its cognate receptor FPr ( Ptgfr ) are implicated as a TGF-β1–independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I ER - Sftpc I73T ) expressing a disease-associated missense mutation in the surfactant protein C ( Sftpc ) gene. Tamoxifen-treated I ER - Sftpc I73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. I ER - Sftpc I73T mice crossed to a Ptgfr- null (FPr –/– ) line showed attenuated weight loss and gene dosage–dependent rescue of mortality compared with FPr +/+ cohorts. I ER -Sftpc I73T /FPr –/– mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an “inflammatory/transitional” cell state in a PGF 2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF 2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

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Section: Resultsmentioning

confidence: 99%

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Rodriguez,

Tang,

Roque Barboza

et al. 2023

JCI Insight

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“…Our group and others have identified monocytes and monocytes-derived moieties as a major population undergoing early expansion during chemical induced fibrogenic responses ( Venosa et al, 2016 ; Misharin et al, 2017 ; Aran et al, 2019 ; Reyfman et al, 2019 ; Joshi et al, 2020 ). We have also shown that monocyte/macrophage moieties play important role in the initial stages of acute exacerbations ( Venosa et al, 2019 ; Venosa et al, 2021 ). The clinical paucity of effective targeted monocyte/macrophage anti-fibrotic therapy suggests that there may be additional key players in the tissue remodeling, particularly in those populations where intrinsic epithelial stress (mutations) drives injury, rather than exogenous triggers.…”

Section: Discussionmentioning

confidence: 87%

Immunophenotyping of Acute Inflammatory Exacerbations of Lung Injury Driven by Mutant Surfactant Protein-C: A Role for Inflammatory Eosinophils

et al. 2022

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Acute inflammatory exacerbations (AIEs) represent immune-driven deteriorations of many chronic lung conditions, including COPD, asthma, and pulmonary fibrosis (PF). The first line of therapy is represented by broad-spectrum immunomodulation. Among the several inflammatory populations mobilizing during AIEs, eosinophils have been identified as promising indicators of an active inflammatory exacerbation. To better study the eosinophil-parenchymal crosstalk during AIE-PF, this work leverages a clinically relevant model of inflammatory exacerbations triggered by inducible expression of a mutation in the alveolar epithelial type 2 cell Surfactant Protein-C gene [SP-CI73T]. Unbiased single-cell sequencing analysis of controls and SP-CI73T mutants at a time coordinated with peak eosinophilia (14 days) defined heightened inflammatory activation, chemotaxis, and survival signaling (IL-6, IL-4/13, STAT3, Glucocorticoid Receptor, mTOR, and MYC) in eosinophils. To study the impact of eosinophils in inflammatory exacerbations, the SP-CI73T line was crossed with eosinophil lineage deficient mice (GATA1Δdbl) to produce the SP-CI73TGATA1KO line. Time course analysis (7–42 days) demonstrated improved lung histology, survival, and reduced inflammation in SP-CI73TGATA1KO cohorts. Spectral flow cytometry of tissue digests confirmed eosinophil depletion in GATA1KO mice and the absence of a compensatory shift in neutrophils and immature monocyte recruitment. Eosinophil deletion resulted in progressive monocyte-derived macrophage accumulation (14 days post-injury), combined with declines in CD3+CD4+ lymphocyte and B220+ B cell abundance. Histochemical analysis revealed atypical inflammatory cell activation in SP-CI73TGATA1KO mice, with reduced numbers of Arg-1+ and iNOS+ cells, but increases in tgfb1 mRNA expression in bronchoalveolar lavage cells and tissue. Dexamethasone treatment (1 mg/kg daily, i.p.) was utilized to investigate corticosteroid efficacy in highly eosinophilic exacerbations induced by mutant SP-CI73T. Dexamethasone successfully reduced total and eosinophil (CD11b+SigF+CD11c−) counts at 14 days and was linked to reduced evidence of structural damage and perivascular infiltrate. Together, these results illustrate the deleterious role of eosinophils in inflammatory events preceding lung fibrosis and demonstrate the efficacy of corticosteroid treatment in highly eosinophilic exacerbations induced by mutant SP-CI73T.

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“…Inflammation is a defense response of the body to stimuli, an important process in the development of tissue damage. When this process continues, the development of a chronic inflammatory state will promote fibrosis formation by increasing proliferation of fibroblast [ 31 , 32 ]. Recent studies have shown that pulmonary fibrosis can be alleviated by altering the inflammatory Milieu [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes

Yang

Gao

et al. 2022

Stem Cell Res Ther

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Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration. Methods To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations. Results IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β. Conclusion IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.

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Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium

Cited by 12 publications

References 65 publications

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Immunophenotyping of Acute Inflammatory Exacerbations of Lung Injury Driven by Mutant Surfactant Protein-C: A Role for Inflammatory Eosinophils

Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes

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