Phagocytosis‐dependent activation of a<scp>TLR</scp>9–<scp>BTK</scp>–calcineurin–<scp>NFAT</scp>pathway co‐ordinates innate immunity to<i>Aspergillus fumigatus</i>

Herbst, Susanne; Shah, Anand; Mazon-Moya, Maria J; Marzola, Vanessa; Jensen, Barbara; Reed, Anna; Birrell, Mark A.; Saijo, Shinobu; Mostowy, Serge; Shaunak, Sunil; Armstrong‐James, Darius

doi:10.15252/emmm.201404556

Cited by 159 publications

(155 citation statements)

References 76 publications

(98 reference statements)

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“…In fact, activation of NFAT proteins has been associated with TLR pathway only in macrophages so far. 37 Cell cycle analyses indicated an increased number of NFAT1-deficient B lymphocytes in S phase when compared to wild-type cells upon PMA/ Ionomycin stimulation (Fig. 2D).…”

Section: Resultsmentioning

confidence: 92%

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

et al. 2016

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The NFAT family of transcription factors has been primarily related to T cell development, activation, and differentiation. Further studies have shown that these ubiquitous proteins are observed in many cell types inside and outside the immune system, and are involved in several biological processes, including tumor growth, angiogenesis, and invasiveness. However, the specific role of the NFAT1 family member in naive B cell proliferation remains elusive. Here, we demonstrate that NFAT1 transcription factor controls Cyclin E expression, cell proliferation, and tumor growth in vivo. Specifically, we show that inducible expression of NFAT1 inhibits cell cycle progression, reduces colony formation, and controls tumor growth in nude mice. We also demonstrate that NFAT1-deficient naive B lymphocytes show a hyperproliferative phenotype and high levels of Cyclin E1 and E2 upon BCR stimulation when compared to wild-type B lymphocytes. NFAT1 transcription factor directly regulates Cyclin E expression in B cells, inhibiting the G1/S cell cycle phase transition. Bioinformatics analysis indicates that low levels of NFAT1 correlate with high expression of Cyclin E1 in different human cancers, including Diffuse Large B-cell Lymphomas (DLBCL). Together, our results demonstrate a repressor role for NFAT1 in cell cycle progression and Cyclin E expression in B lymphocytes, and suggest a potential function for NFAT1 protein in B cell malignancies.

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Section: Resultsmentioning

confidence: 92%

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

et al. 2016

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“…Af phagocytosis activates NFAT nuclear translocation in murine macrophages (4 Figure E1D). Maximum translocation of NFATc2 to the nucleus was seen in response to Af at 60 minutes postinfection.…”

Section: A Fumigatus Activates Calcineurin-nfat-dependent Inflammatomentioning

confidence: 99%

“…To determine whether this phenomenon occurred in vivo, we exploited our zebrafish invasive aspergillosis model (4). Using an mpeg:mCherry transgenic zebrafish line and enhanced green fluorescent protein-expressing Af, we examined the macrophage-Af interaction in vivo using time-lapse high-resolution confocal microscopy.…”

Section: Video 1)mentioning

confidence: 99%

“…Normally inhaled conidia are cleared by alveolar macrophages to prevent fungal germination, tissue invasion, and destructive lung disease (2,3). Our previous work with murine and zebrafish models of invasive aspergillosis showed the importance of macrophages in control of Af early postinfection, with neutrophil influx as a later event (4,5). Previous studies have highlighted the importance of inflammatory monocytes in murine invasive aspergillosis (6).…”

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confidence: 99%

“…We have previously shown that calcineurin inhibitor immunosuppressants (FK506 [tacrolimus]) increase susceptibility to murine PA through inhibition of the macrophage Toll-like receptor 9-calcineurin-NFAT pathway (4,5). This pathway is crucial for activation of inflammatory responses to Af and for recruitment of fungicidal neutrophils to the site of infection.…”

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confidence: 99%

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Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

Shah

Kannambath

Herbst

et al. 2016

Am J Respir Crit Care Med

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Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis.Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants. Methods:We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies.Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape.Conclusions: These observations identify programmed, necrosisdependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.

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Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes

Bendíčková

Tidu

Zuani

et al. 2019

Journal of Leukocyte Biology

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Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN‐NFAT by cyclosporine A significantly reduced monocyte production of TNF‐α, IL‐10, and MCP‐1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin‐3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT‐dependent pentraxin‐3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte‐mediated defenses against fungal infection in immune‐suppressed patients.

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Phagocytosis‐dependent activation of aTLR9–BTK–calcineurin–NFATpathway co‐ordinates innate immunity toAspergillus fumigatus

Cited by 159 publications

References 76 publications

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes

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