IκBζ is an essential mediator of immunity to oropharyngeal candidiasis

Taylor, Tiffany C.; Coleman, Bianca M.; Arunkumar, Samyuktha P.; Dey, Ipsita; Dillon, John T.; Ponde, Nicole O.; Poholek, Amanda C.; Schwartz, Daniella M.; McGeachy, Mandy J.; Conti, Heather R.; Gaffen, Sarah L.

doi:10.1016/j.chom.2023.08.016

Cited by 7 publications

(5 citation statements)

References 104 publications

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“…Hematopoietic-derived TREM2 is indispensable for protection against OPC Previous studies have suggested an inhibitory role for TREM2 in tumor immunity [26][27][28]. Findings from the OPC mouse model demonstrate the complete clearance of C. albicans by Day 5 [29]. Intriguingly, during the early stages of OPC (Day 1), we observed an accumulation of TREM2-expressing macrophages (Extended Data Fig.…”

Section: Induced Transcription Of Trem2 Predominantly Situated At The...mentioning

confidence: 52%

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TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal Candidiasis

Deng,

Chen,

Liu

et al. 2024

Preprint

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The landscape of oral mucosal immunity, particularly in the context of oropharyngeal candidiasis (OPC), remains largely uncharted. By employing single-cell RNA sequencing (scRNA-seq) on murine models of OPC, we have illuminated the immune dynamics within this niche. We discovered a new subpopulation: TREM2-expressing macrophages, intrinsic to the oral mucosa, which infiltrated in response to Candida albicans (C. albicans) infection. However, these macrophages were significantly depleted under cortisone acetate (CA)-induced immunosuppression. This study unveiled the pattern recognition receptor (PRR) characteristics of TREM2 during OPC, where TREM2 demonstrated the ability to directly recognize candidalysin at positions G65, N73, and N91-K92, inducing downstream inflammatory signaling regulation of TNF-α, which orchestrated macrophage and neutrophil responses and influenced Th17 cell differentiation. As a result, the absence of TREM2 increases the susceptibility of mice to OPC. Conversely, administering TREM2 agonists has been shown to facilitate the clearance of OPC induced by CA in mice. Therefore, our findings expand the understanding of TREM2 beyond its known association with neurodegenerative diseases and metabolic disorders, positioning it as a key receptor in bridging the host-fungus immune interface, and providing novel therapeutic insights for glucocorticoid-induced OPC.

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Section: Induced Transcription Of Trem2 Predominantly Situated At The...mentioning

confidence: 52%

“…The construction of the mouse OPC model was based on previously reported methods in the literature [6, 29,47,77]. Three days before infection, a monoclonal culture of C. albicans (SC5314) was transferred into 10 ml of YPD liquid medium and incubated at 30°C on a shaker.…”

Section: Opc Modelmentioning

confidence: 99%

TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal Candidiasis

Deng,

Chen,

Liu

et al. 2024

Preprint

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“…Understanding the earliest stages of host-fungal interactions is critical, and epithelial cells are some of the first cells to encounter conidia upon infection, along with AMs. In mucosal infection with Candida albicans , oral epithelial cells are known to respond to IL-17 signaling and produce anti-microbial peptides, 38,39 and pulmonary epithelial cells use NF-κB signaling to promote innate lymphocyte antifungal responses during Blastomyces infection. 15 However, the mechanisms by which epithelial cells communicate with neutrophils to regulate effector properties in situ remained undefined.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity toAspergillus fumigatus

Mills,

Westermann,

Espinosa

et al. 2024

Preprint

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Aspergillus fumigatus causes life-threatening mold pneumonia in immune compromised patients, particularly in those with quantitative or qualitative defects in neutrophils. While innate immune cell crosstalk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced IL-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF-responsive neutrophils, with the latter being essential for host survival. Our findings establish SPC+ epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens.

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“…Our assessment of SPRR2a (one of the few SPRRs for which detection reagents are available), showed prominent expression in the oral epithelium during OPC. Oral epithelial cells (OECs) are key responders to Type 17 cytokines, yet there is a clear separation of cytokine-responsive cell types within this tissue [ 17 , 36 , 37 ]. Specifically, while IL-17 signals in the superficial, K13 + post-mitotic OEC layer via the IκBζ transcription factor [ 23 , 36 ], IL-22 is required mainly on the proliferating K14 + basal stem-like cell layer [ 17 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Oral epithelial cells (OECs) are key responders to Type 17 cytokines, yet there is a clear separation of cytokine-responsive cell types within this tissue [ 17 , 36 , 37 ]. Specifically, while IL-17 signals in the superficial, K13 + post-mitotic OEC layer via the IκBζ transcription factor [ 23 , 36 ], IL-22 is required mainly on the proliferating K14 + basal stem-like cell layer [ 17 , 36 ]. Admittedly, this view of oral epithelial cell dynamics is overly simplistic, as cells in the basal layer undergo complex transitional states during differentiation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Combinatorial actions of IL-22 and IL-17 drive optimal immunity to oral candidiasis through SPRRs

Aggor,

Bertolini,

Coleman

et al. 2024

PLoS Pathog

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Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs.

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IκBζ is an essential mediator of immunity to oropharyngeal candidiasis

Cited by 7 publications

References 104 publications

TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal Candidiasis

TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal Candidiasis

GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity toAspergillus fumigatus

Combinatorial actions of IL-22 and IL-17 drive optimal immunity to oral candidiasis through SPRRs

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