Transcriptional analysis of Foxp3+ Tregs and functions of two identified molecules during resolution of ALI

Mock, Jason R.; Dial, Catherine F.; Tune, Miriya K; Norton, D.; Martin, Jessica R.; Gomez, John C.; Hagan, Robert S.; Dang, Hong; Doerschuk, Claire M.

doi:10.1172/jci.insight.124958

Cited by 28 publications

(44 citation statements)

References 59 publications

(106 reference statements)

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“…In the same lung digests, Ifng −/− lungs contained fewer CD8 + lymphocytes at day 4 and 7 post LPS, and fewer CD3 + and CD4 + lymphocytes on day 7 (Figure l–n), as identified by flow cytometry with gating as previously reported (Mock et al, ). There was no significant difference in the number of lung Foxp3 + Tregs between genotypes, and Tregs increased in both genotypes on day 7 during resolution (Figure o).…”

Section: Resultssupporting

confidence: 81%

“…We and others have demonstrated that Tregs play an essential role in the resolution of ALI (D'Alessio et al, ; Dial et al, ; Lin, Wu, Wang, Xiao, & Xu, ; Mock et al, ). Following LPS injury, Tregs are increased on day 7 in WT mice (Mock et al, ). Despite the fact that Tregs can regulate the expression of IFN‐γ and that IFN‐γ can regulate Treg functions (Overacre‐Delgoffe et al, ; Panduro, Benoist, & Mathis, ; Sojka & Fowell, ), IFN‐γ does not affect the numbers of Tregs after LPS or S. pneumoniae .…”

Section: Discussionmentioning

confidence: 99%

“…Lungs were inflated to 25 cm H 2 O and fixed with 10% formalin (ThermoFisher) for histological evaluation by hematoxylin and eosin staining (D'Alessio et al, ; Mock et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…Misharin et al (2013). (f) Changes in CD3 + , CD4 + , CD8 + , Foxp3 + , γδ + , CD19 + , NK T lymphocyte subsets, or NK cells as total numbers in single-cell suspensions determined using a previously published lymphocyte flow cytometric panel and gating approach (Mock et al, 2019). Data are expressed as the mean ± SEM.…”

Section: The Effects Of Ifn-γ On Immune Cell Kinetics During Ali Inmentioning

confidence: 99%

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Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

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The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

“…Lungs were inflated to 25 cm H 2 O and fixed with 10% formalin (ThermoFisher) for histological evaluation by hematoxylin and eosin staining (D'Alessio et al, ; Mock et al, ).…”

Section: Methodsmentioning

confidence: 99%

Section: The Effects Of Ifn-γ On Immune Cell Kinetics During Ali Inmentioning

confidence: 99%

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Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

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“…Aside from their role in maintaining immune homeostasis through their capacity to suppress over-exuberant immune system activation, Treg cells reside in healthy tissues and accumulate in the lung in response to viral injury to promote tissue repair (5,6). Our group and others have shown that in murine models of lung injury, Treg cells are master orchestrators of recovery (7)(8)(9)(10). Treg cells are capable of promoting tissue regeneration and repair, at least in part through release of reparative mediators such as the epidermal growth factor receptor ligand amphiregulin (Areg), which induces cell proliferation and differentiation of the injured tissue (11).…”

Section: Immunomodulatory Regulatory T (Treg) Cells Expressing the LImentioning

confidence: 99%

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Morales‐Nebreda¹,

Helmin²,

Markov³

et al. 2020

Preprint

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Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairment of reparative Treg cell function following experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provide insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Novel strategies that restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

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Aorta Regulatory T Cells with a Tissue‐Specific Phenotype and Function Promote Tissue Repair through Tff1 in Abdominal Aortic Aneurysms

Xia

et al. 2022

Advanced Science

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In addition to maintaining immune tolerance, Foxp3+ regulatory T cells (Tregs) perform specialized functions in tissue homeostasis and remodeling. However, whether Tregs in aortic aneurysms have a tissue‐specific phenotype and function is unclear. Here, a special group of Tregs that potentially inhibit abdominal aortic aneurysm (AAA) progression are identified and functionally characterized. Aortic Tregs gradually increase during the process of AAA and are mainly recruited from peripheral circulation. Single‐cell TCR sequencing and bulk RNA sequencing demonstrate their unique phenotype and highly expressed trefoil factor 1 (Tff1). Foxp3cre/creTff1flox/flox mice are used to clarify the role of Tff1 in AAA, suggesting that aortic Tregs secrete Tff1 to regulate smooth muscle cell (SMC) survival. In vitro experiments confirm that Tff1 inhibits SMC apoptosis through the extracellular signal‐regulated kinase (ERK) 1/2 pathway. The findings reveal a tissue‐specific phenotype and function of aortic Tregs and may provide a promising and novel approach for the prevention of AAA.

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Transcriptional analysis of Foxp3+ Tregs and functions of two identified molecules during resolution of ALI

Cited by 28 publications

References 59 publications

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Aorta Regulatory T Cells with a Tissue‐Specific Phenotype and Function Promote Tissue Repair through Tff1 in Abdominal Aortic Aneurysms

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