Resolving lung injury: a new role for Tregs in controlling the innate immune response

Pietropaoli, Anthony P.; Georas, Steve N.

doi:10.1172/jci40880

Cited by 13 publications

(13 citation statements)

References 31 publications

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“…Previously, T lymphocytes were considered largely irrelevant for ALI, because nude and RAG-1 2/2 mice showed the same ALI phenotype as wt animals (24,25). More recently, a critical role of T, but not B, lymphocytes for the resolution of ALI became apparent (26,27). Our data extend these findings as we show that not only the lack, but also the proinflammatory properties of lymphocytes (CREMa dependent) can exacerbate ALI in the acute as well as during the resolution phase.…”

Section: Discussionsupporting

confidence: 85%

Overexpression of CREMα in T Cells Aggravates Lipopolysaccharide-Induced Acute Lung Injury

Verjans

Ohl

Yin

et al. 2013

The Journal of Immunology

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Transcription factor cAMP response element modulator (CREM)α contributes to various cellular and molecular abnormalities in T cells, including increased IL-17 and decreased IL-2 expression. For development of acute lung injury (ALI), the invasion and regulation of immune cells are highly important, but the role of T cells remains unclear. In this study, we show that CREMα is upregulated in LPS-induced ALI. During the early phase of ALI (day 1), T cell–specific CREMα overexpression enhances the numbers of T cells and expression of TNF-α in bronchoalveolar lavage fluid and deteriorates lung functions. On day 3 of ALI, CREMα transgenic mice present a stronger inflammatory response with higher levels of TNF-α, IL-6, and IL-17 correlating with increased numbers of T cells and neutrophils in bronchoalveolar lavage fluid, whereas expression of Foxp3 and IL-2 and numbers of regulatory T cells are decreased. These changes result in restricted lung function in CREMα transgenic mice. Finally, an adoptive transfer of CREM−/− CD4+ T cells, but not of wild-type T cells into RAG-1−/− mice results in ameliorated disease levels. Thus, levels of CREM in T cells determine the outcome of ALI, and CREMα transgenic animals represent a model in which proinflammatory T cells aggravate ALI in different phases of the disease. Given the fact that patients with autoimmune diseases like systemic lupus erythematosus show higher levels of CREMα and an increased susceptibility toward infectious complications, our finding is of potential clinical significance and may enable new therapeutic strategies.

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Section: Discussionsupporting

confidence: 85%

Overexpression of CREMα in T Cells Aggravates Lipopolysaccharide-Induced Acute Lung Injury

Verjans

Ohl

Yin

et al. 2013

The Journal of Immunology

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“…Detection of Tregs based upon their positive expression of CD3, CD4 and CD25 and downregulated CD127 expression (rather than expression of the transcription factor, FoxP3), was based upon reports that FoxP3 expression may prove unreliable as a marker of human Tregs as it appears to define a number of functionally heterogeneous populations which differ in their suppressive function and activation status [30,31]. Tregs are proposed to play a role in the resolution of lung inflammation [32], and therefore it seems fitting that these cells are reduced during the acute inflammatory response alongside heightened neutrophilia and increased iPMLCs. It is interesting to speculate that a prolonged and heightened expression of iPMLCs (and reduced Tregs) may be responsible for disease pathology in conditions of chronic lung inflammation and scarring, such as IPF.…”

Section: Discussionmentioning

confidence: 99%

A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation

Brittan¹,

Barr²,

Morris³

et al. 2012

Eur Respir J

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The co-ordinated recruitment of monocyte subpopulations, neutrophils and regulatory T-cells (Tregs) during the early stages of human acute lung inflammation remains poorly understood. We therefore performed a detailed characterisation of these lineages in the blood and lungs in a model of human acute lung inflammation.Healthy volunteers inhaled lipopolysaccharide (LPS) or saline (n56 for each group). Blood was collected at 0, 2, 4, 6 and 8 h and bronchoscopy with bronchoalveolar lavage (BAL) performed at 8 h. Multiparameter flow cytometry was used to characterise monocyte subpopulations, neutrophils and Tregs in the blood and lung.Inhalation of LPS was associated with significant blood and BAL fluid neutrophilia. Blood populations of monocyte subpopulations and Tregs were unaltered by LPS. In contrast, LPS induced an accumulation of a pulmonary monocyte-like cell (PMLC) population, which was further subdivided into ''inducible'' CD14 ++ CD16 -and ''resident'' CD14 ++ CD16 + subsets. Inducible PMLCs were significantly increased following LPS inhalation (p50.0046), whereas resident PMLCs were unchanged. In addition, we noted a significant decrease in Tregs in BAL fluid with LPS inhalation (p50.027).The early stages of LPS-induced inflammation in humans is characterised by pulmonary accumulation of a novel inducible monocyte-like subpopulation, accompanied by significant changes in both neutrophil and Treg numbers.

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“…3B). The findings from animal models have suggested that recovery from acute lung injury involves upregulation of T Regs [47].…”

Section: Tnf-a For 48 Hours and Subsequently Used In Cocultures Withmentioning

confidence: 99%

In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome

Simonson

Mougiakakos

Heldring

et al. 2015

Stem Cells Translational Medicine

137

120

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A detailed analysis was performed of the immunomodulatory and proteomic profiles of mesenchymal stromal cells (MSCs) administered to two patients with refractory acute respiratory distress syndrome (ARDS). The respiratory, hemodynamic, and multiorgan failure resolved and multiple pulmonary and systemic inflammation markers decreased. These observations highlight the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects.

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Resolving lung injury: a new role for Tregs in controlling the innate immune response

Cited by 13 publications

References 31 publications

Overexpression of CREMα in T Cells Aggravates Lipopolysaccharide-Induced Acute Lung Injury

Overexpression of CREMα in T Cells Aggravates Lipopolysaccharide-Induced Acute Lung Injury

A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation

In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome

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