Frontline Science: Coincidental null mutation of <i>Csf2rα</i> in a colony of PI3Kγ−/− mice causes alveolar macrophage deficiency and fatal respiratory viral infection

Schneider, Christoph; Nobs, Samuel Philip; Heer, Alex K.; Hirsch, Emilio; Penninger, Josef; Siggs, Owen M.

doi:10.1189/jlb.4hi0316-157r

Cited by 26 publications

(35 citation statements)

References 32 publications

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“…23 However, while mTOR is important for the development of AM, upstream PI3K-signaling was found to be dispensable. 24 This contrasted with our findings in lung dendritic cells (DCs) where we recently described a PI3K--Akt1-mTOR-signaling axis essential for their development. 25 Deletion of PPAR-at later stages of AM development using a Cre-driven by CD11c, which is only expressed perinatally, leads to the appearance of a population of arrested AM.…”

Section: Ppar-and Alveolar Macrophage Developmentcontrasting

confidence: 92%

“…Interestingly, a recent publication described mTOR, another regulator of metabolism, to be important for development and function of AM as well . However, while mTOR is important for the development of AM, upstream PI3K‐signaling was found to be dispensable . This contrasted with our findings in lung dendritic cells (DCs) where we recently described a PI3K‐γ‐Akt1‐mTOR‐signaling axis essential for their development .…”

Section: Introductioncontrasting

confidence: 76%

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PPAR-γ in innate and adaptive lung immunity

Nobs

Köpf²

2018

Journal of Leukocyte Biology

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The transcription factor PPAR-γ (peroxisome proliferator-activated receptor-γ) is a key regulator of lung immunity exhibiting multiple cell type specific roles in controlling development and function of the lung immune system. It is strictly required for the generation of alveolar macrophages by controlling differentiation of fetal lung monocyte precursors. Furthermore, it plays an important role in lung allergic inflammation by licensing lung dendritic cell t helper 2 (Th2) priming capacity as well as acting as a master transcription factor for pathogenic Th2 cells. Due to this plethora of functions and its involvement in multiple pulmonary diseases including asthma and pulmonary alveolar proteinosis, understanding the role of PPAR-γ in lung immunity is an important subject of ongoing research.

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Section: Ppar-and Alveolar Macrophage Developmentcontrasting

confidence: 92%

Section: Introductioncontrasting

confidence: 76%

PPAR-γ in innate and adaptive lung immunity

Nobs

Köpf²

2018

Journal of Leukocyte Biology

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“…Csf2ra À/À mice were recently established in our laboratory (Schneider et al, 2017). Csf2ra À/À mice were recently established in our laboratory (Schneider et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

“…Mice C57BL/6 CD45.2 and congenic CD45.1 mice were originally from the Jackson Laboratory. Csf2ra À/À mice were recently established in our laboratory (Schneider et al, 2017). Csf2rb À/À mice (Stanley et al, 1994) were originally provided by A. Dunn, Ludwig Institute for Cancer Research, Victoria, Australia, and backcrossed to C57BL/6 in our facility.…”

Section: Methodsmentioning

confidence: 99%

Fetal monocytes possess increased metabolic capacity and replace primitive macrophages in tissue macrophage development

Okreglicka

Pohlmeier

et al. 2020

The EMBO Journal

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Tissue-resident macrophages (MΦ TR ) originate from at least two distinct waves of erythro-myeloid progenitors (EMP) arising in the yolk sac (YS) at E7.5 and E8.5 with the latter going through a liver monocyte intermediate. The relative potential of these precursors in determining development and functional capacity of MΦ TR remains unclear. Here, we studied development of alveolar macrophages (AM) after single and competitive transplantation of different precursors from YS, fetal liver, and fetal lung into neonatal Csf2ra À/À mice, which lack endogenous AM. Fetal monocytes, promoted by Myb, outcompeted primitive MΦ (pMΦ) in empty AM niches and preferentially developed to mature AM, which is associated with enhanced mitochondrial respiratory and glycolytic capacity and repression of the transcription factors c-Maf and MafB. Interestingly, AM derived from pMΦ failed to efficiently clear alveolar proteinosis and protect from fatal lung failure following influenza virus infection. Thus, our data demonstrate superior developmental and functional capacity of fetal monocytes over pMΦ in AM development and underlying mechanisms explaining replacement of pMΦ in fetal tissues.

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“…AM precursors develop mainly from fetal monocytes, which seed the lung prior to birth and massively expand and develop into mature macrophages in response to granulocytemacrophage colony-stimulating factor (GM-CSF) and transforming growth factor ␤ (TGF-␤) after birth (18)(19)(20). A number of factors, including PPAR-␥, mTORC1, the phosphoinositide kinase PIKfyve, and L-plastin, were also recently shown to be important in AM development and function (19,(21)(22)(23)(24). Interestingly, AM appear to be essential for protection against IAV and other respiratory viral infections (25)(26)(27)(28)(29)(30)(31).…”

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confidence: 99%

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection

Huang

Zhu

Cheon

et al. 2019

J Virol

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Alveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-␥ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-␥ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-␥ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-␥ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-␥ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-␥ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-␥ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-␥ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-␥ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-␥ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections.A cute respiratory viral infections, such as influenza A virus (IAV) and respiratory syncytial virus (RSV) infections, cause severe morbidity and mortality and are among leading causes of death in children and the elderly (1, 2). Particularly, IAV

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Frontline Science: Coincidental null mutation of Csf2rα in a colony of PI3Kγ−/− mice causes alveolar macrophage deficiency and fatal respiratory viral infection

Cited by 26 publications

References 32 publications

PPAR-γ in innate and adaptive lung immunity

PPAR-γ in innate and adaptive lung immunity

Fetal monocytes possess increased metabolic capacity and replace primitive macrophages in tissue macrophage development

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection

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