The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Aspergillus fumigatus Airway Infection

Ralph, Benjamin; Lehoux, Mélanie; Ostapska, Hanna; Snarr, Brendan D.; Caffrey-Carr, Alayna K.; Fraser, Richard S.; Saleh, Maya; Obar, Joshua J.; Qureshi, Salman T.; Sheppard, Donald C.

doi:10.3389/fimmu.2021.675294

Cited by 12 publications

(9 citation statements)

References 41 publications

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“…IL1RN encodes IL1 receptor antagonist (IL1RA), which inhibits the activity of IL1α/β signaling by binding to interleukin-1 receptor 1 (IL1R1) and preventing IL-1 mediated signaling. In a murine model of acute lung injury, Il1rn -/mice exhibit delayed resolution of inflammation and increased numbers of neutrophils in lung tissue 52 , and IL1 signaling has been implicated in neutrophil longevity in a preclinical model of Aspergillus fumigatus infection 53 . Aged neutrophils from RSVposP subjects demonstrated a unique transcriptional profile, enriched with protease inhibitors (i.e., SLPI, PI3, and CSTB), ORM1 (an acute phase reactant of uncertain immunoregulatory function 54 ), and TNFAIP2 (an inhibitor of TNF signaling 55 ).…”

Section: Discussionmentioning

confidence: 99%

Single Cell Analysis Identifies Distinct Profiles in Pediatric Acute Respiratory Distress Syndrome

Flerlage

Crawford

Allen

et al. 2022

Preprint

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Acute respiratory distress syndrome (ARDS), termed pediatric ARDS (pARDS) in children, is a severe form of acute respiratory failure (ARF) that is associated with significant morbidity and mortality. Pathologic immune responses have been implicated in the development of pARDS. Here, we present a unique description of microbial sequencing and single cell gene expression in tracheal aspirates (TAs) obtained longitudinally from infants admitted to the pediatric intensive care unit (PICU) with ARF. Important alterations in TA epithelial cell, mononuclear phagocyte (MNP), and neutrophil transcription were associated with subjects’ illness severity, etiology (of ARF), and sampling time point. Specifically, in patients with moderate to severe pARDS compared to those with no to mild pARDS we identified reduced interferon stimulated gene (ISG) and cytokine expression in epithelial cells, reduced development over time of a regulatory IL-10 expressing macrophage population, and progressive airway neutrophilia associated with a unique transcriptional profile in aged neutrophils. In addition, we incorporated viral capture sequencing (ViroCap) with single cell transcriptomic analysis to explore interactions between respiratory syncytial virus (RSV) and host cells in infected and bystander epithelia. Our findings indicate that pARDS is defined by distinct inflammatory cell profiles that are etiology- and severity-dependent and implicate inadequate induction of ISGs, cytokines/chemokines, and repair-associated macrophage transcriptional programs in the pathogenesis of moderate to severe pARDS.

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Section: Discussionmentioning

confidence: 99%

Single Cell Analysis Identifies Distinct Profiles in Pediatric Acute Respiratory Distress Syndrome

Flerlage

Crawford

Allen

et al. 2022

Preprint

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“…Yet, we cannot exclude the possibility that IL-22 is involved in the response to C. albicans post-irradiation. Additionally, IL-1/IL-1R have been implicated in driving the neutrophil response in forms of candidiasis, as well as other fungal infections [ 48 , 52 , 53 , 54 , 55 , 56 ]. Here, we show that increased neutrophils are pathophysiological during OPC, which aligns with the understanding of these cells during VVC and supports the dynamic nature of tissue-specific neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Saul-McBeth

Dillon

Launder

et al. 2022

JoF

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Fungal infections caused by Candida albicans are a serious problem for immunocompromised individuals, including those undergoing radiotherapy for head and neck cancers. Targeted irradiation causes inflammatory dysregulation and damage to the oral mucosa that can be exacerbated by candidiasis. Post-irradiation the cytokine interleukin-17 (IL-17) protects the oral mucosae by promoting oral epithelial regeneration and balancing the oral immune cell populations, which leads to the eventual healing of the tissue. IL-17 signaling is also critical for the antifungal response during oropharyngeal candidiasis (OPC). Yet, the benefit of IL-17 during other forms of candidiasis, such as vulvovaginal candidiasis, is not straightforward. Therefore, it was important to determine the role of IL-17 during OPC associated with radiation-induced inflammatory damage. To answer this question, we exposed Il17ra−/− and wild-type mice to head-neck irradiation (HNI) and OPC to determine if the IL-17 signaling pathway was still protective against C. albicans. HNI increased susceptibility to OPC, and in Il17ra−/− mice, the mucosal damage and fungal burden were elevated compared to control mice. Intriguingly, neutrophil influx was increased in Il17ra−/− mice, yet these cells had reduced capacity to phagocytose C. albicans and failed to clear OPC compared to immunocompetent mice. These findings suggest that radiotherapy not only causes physical damage to the oral cavity but also skews immune mediators, leading to increased susceptibility to oropharyngeal candidiasis.

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“…Nevertheless, the roles of G-CSF and neutrophils during infection are very complicated. G-CSF is reported to be beneficial in a mouse model of A. fumigatus airway infection (Polak-Wyss, 1991;Ralph et al, 2021). However, G-CSF might not simply associate with similar protective effects in humans.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Aspergillus fumigatus Germination by Neutrophils Is Enhanced by Endothelial-Derived CSF3 Production

Zhang

Wei

et al. 2022

Front. Microbiol.

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Infection with Aspergillus fumigatus can cause life-threatening diseases in immunocompromised patients with an unacceptable mortality rate. Angioinvasion is one of the features of severe invasive aspergillosis. Neutrophils are short-lived immune cells regulated by colony-stimulating factor 3 (CSF3) that play a key role in anti-fungal immune responses. To investigate the interactions between A. fumigatus and the host immune cells, such as neutrophils, we stimulated human umbilical vein endothelial cells (HUVECs) with the conidia of A. fumigatus, and co-cultured them with human neutrophils. Apoptosis and functions of neutrophils were analyzed. Our results showed that HUVECs upregulate the expression of CSF3, which could reduce the apoptosis of neutrophils while enhancing their functions. Lack of CSF3 was associated with enhanced apoptosis of neutrophils with impaired function. This work indicated that the CSF3 is required for neutrophil survival and function, at least in the early stages of A. fumigatus infection.

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The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Aspergillus fumigatus Airway Infection

Cited by 12 publications

References 41 publications

Single Cell Analysis Identifies Distinct Profiles in Pediatric Acute Respiratory Distress Syndrome

Single Cell Analysis Identifies Distinct Profiles in Pediatric Acute Respiratory Distress Syndrome

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Suppression of Aspergillus fumigatus Germination by Neutrophils Is Enhanced by Endothelial-Derived CSF3 Production

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