Pulmonary Mycosis Drives Forkhead Box Protein A2 Degradation and Mucus Hypersecretion through Activation of the Spleen Tyrosine Kinase–Epidermal Growth Factor Receptor–AKT/Extracellular Signal-Regulated Kinase 1/2 Signaling

Choi, Won Chul; Yang, Aiqin; Sieve, Aaron; Kuo, Shanny Hsuan; Mudalagiriyappa, Srinivasu; Vieson, Miranda D.; Maddox, Carol W.; Nanjappa, Som G.; Lau, Gee W.

doi:10.1016/j.ajpath.2020.09.013

Cited by 4 publications

(5 citation statements)

References 98 publications

(135 reference statements)

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“…PI3K is crucial for both outputs while Syk only mediates the production of cytokines ( 80 ), indicating a role for PI3K in the generation of ROS in a Syk-independent manner (discussed below), but also in the production of cytokines relying on Syk. This Dectin-1/Syk/PI3K pathway involved in cytokine production has been described in response to the fungi Fusarium proliferatum ( 81 ) and Blastomyces dermatitidis ( 82 ).…”

Section: Signaling Pathways Downstream Dectin-1mentioning

confidence: 99%

Dectin-1 Signaling Update: New Perspectives for Trained Immunity

2022

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The C-type lectin receptor Dectin-1 was originally described as the β-glucan receptor expressed in myeloid cells, with crucial functions in antifungal responses. However, over time, different ligands both of microbial-derived and endogenous origin have been shown to be recognized by Dectin-1. The outcomes of this recognition are diverse, including pro-inflammatory responses such as cytokine production, reactive oxygen species generation and phagocytosis. Nonetheless, tolerant responses have been also attributed to Dectin-1, depending on the specific ligand engaged. Dectin-1 recognition of their ligands triggers a plethora of downstream signaling pathways, with complex interrelationships. These signaling routes can be modulated by diverse factors such as phosphatases or tetraspanins, resulting either in pro-inflammatory or regulatory responses. Since its first depiction, Dectin-1 has recently gained a renewed attention due to its role in the induction of trained immunity. This process of long-term memory of innate immune cells can be triggered by β-glucans, and Dectin-1 is crucial for its initiation. The main signaling pathways involved in this process have been described, although the understanding of the above-mentioned complexity in the β-glucan-induced trained immunity is still scarce. In here, we have reviewed and updated all these factors related to the biology of Dectin-1, highlighting the gaps that deserve further research. We believe on the relevance to fully understand how this receptor works, and therefore, how we could harness it in different pathological conditions as diverse as fungal infections, autoimmunity, or cancer.

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Section: Signaling Pathways Downstream Dectin-1mentioning

confidence: 99%

Dectin-1 Signaling Update: New Perspectives for Trained Immunity

2022

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“…Responses of airway epithelium to Coccidioides have not been reported in human or animal models. Investigations into Blastomyces, Histoplasma , and Paracoccidioides primarily utilize experimental models rather than human airway epithelial cell systems [ 79 , 80 ]. Opportunistic fungal infections, especially Aspergillus spp., and human airway epithelial cells are more commonly studied compared to endemic fungi, but limited information is available for Cryptococcus , Mucor , Rhizopus , and Pneumocystis .…”

Section: The Human Airway Epithelium Is a Key Player In The Host-fung...mentioning

confidence: 99%

Human Airway Epithelium Responses to Invasive Fungal Infections: A Critical Partner in Innate Immunity

Crossen

Ward

Reedy

et al. 2022

JoF

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The lung epithelial lining serves as the primary barrier to inhaled environmental toxins, allergens, and invading pathogens. Pulmonary fungal infections are devastating and carry high mortality rates, particularly in those with compromised immune systems. While opportunistic fungi infect primarily immunocompromised individuals, endemic fungi cause disease in immune competent and compromised individuals. Unfortunately, in the case of inhaled fungal pathogens, the airway epithelial host response is vastly understudied. Furthering our lack of understanding, very few studies utilize primary human models displaying pseudostratified layers of various epithelial cell types at air-liquid interface. In this review, we focus on the diversity of the human airway epithelium and discuss the advantages and disadvantages of oncological cell lines, immortalized epithelial cells, and primary epithelial cell models. Additionally, the responses by human respiratory epithelial cells to invading fungal pathogens will be explored. Future investigations leveraging current human in vitro model systems will enable identification of the critical pathways that will inform the development of novel vaccines and therapeutics for pulmonary fungal infections.

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“…[1][2][3][4][5] In recent years, FoxA2 proved to be crucially involved in several metabolic processes (bile acids and lipids homeostasis, clearance of fatty acids, response to insulin and many others), and its expression has been demonstrated in many tumour types (neuroendocrine lung and prostate tumours, colorectal carcinoma, breast carcinoma, melanoma and many others). [1][2][3][4][5][6][7][8][9][10][11][12] Nettersheim et al found that FoxA2 plays a key role in the progression from seminoma (S) to non-seminomatous germ cell tumours of the testis (NSGCTT), the so-called 'reprogramming' of S cells. [13][14][15][16] Specifically, FoxA2 regulates the expression of genes associated with yolk sac tumour (YST) differentiation [SRY-box 17 (SOX17), glypican-3 (GPC3), afetoprotein (AFP) and others] and is a putative effector of the YST phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…It is a pivot molecule in embryonic development that regulates the formation of the notochord, nervous system and several endodermal structures 1–5 . In recent years, FoxA2 proved to be crucially involved in several metabolic processes (bile acids and lipids homeostasis, clearance of fatty acids, response to insulin and many others), and its expression has been demonstrated in many tumour types (neuroendocrine lung and prostate tumours, colorectal carcinoma, breast carcinoma, melanoma and many others) 1–12 . Nettersheim et al .…”

Section: Introductionmentioning

confidence: 99%

FoxA2 is a reliable marker for the diagnosis of yolk sac tumour postpubertal‐type

Ricci,

Ambrosi,

Franceschini

et al. 2023

Histopathology

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AimsYolk sac tumour postpubertal‐type (YSTpt) shows a wide range of histological patterns and is challenging to diagnose. Recently, forkhead box transcription factor A2 (FoxA2) emerged as a driver of YSTpt formation and a promising marker for diagnosing YSTpt. However, FoxA2 has not been tested in the different patterns of YSTpt. This study aimed to assess the staining pattern of FoxA2 in te different patterns of YSTpt and other germ cell tumours of the testis (GCTT), comparing it with glypican‐3 (GPC3) and α‐fetoprotein (AFP).Methods and resultsFOXA2, GPC3 and AFP immunohistochemistry was performed on 24 YSTpt (24 microcystic/reticular, 10 myxoid, two macrocystic, five glandular/alveolar, two endodermal sinus/perivascular, four solid, two polyembryoma/embryoid body and two polyvesicular vitelline) and 81 other GCTT. The percentage of positive cells (0, 1+, 2+, 3+) and the intensity (0, 1, 2, 3) were evaluated regardless of and within each YSTpt pattern. FoxA2 was positive in all YSTpt (24 of 24) and all but one (23 of 24) exhibited 2+/3+ stain, with higher intensity [median value (mv): 2.6] than AFP (1.8) and GPC3 (2.5). Both FoxA2 and GPC3 were positive in all microcystic/reticular (24 of 24), myxoid (10 of 10), macrocystic (two of two), endodermal sinus/perivascular (four of four) and polyembryoma/embryoid body (two of two) patterns. Nevertheless, only FoxA2 was positive in all glandular/alveolar (five of five), solid (four of four) and polyvesicular vitelline (two of two) patterns. The intensity of FoxA2 was higher than AFP and GPC3 in almost all YST patterns. In the other GCTT, FoxA2 was positive only in teratoma postpubertal‐type (Tpt) [13 of 20 (65%)], with staining almost exclusively confined to the mature gastrointestinal/respiratory tract epithelium.ConclusionsFoxA2 is a highly sensitive and specific biomarker that supports the diagnosis of YSTpt. FoxA2 is superior to GPC3 and AFP, especially in rare and difficult‐to‐diagnose histological patterns of YSTpt, but mature glands of Tpt could represent a potential diagnostic pitfall.

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Pulmonary Mycosis Drives Forkhead Box Protein A2 Degradation and Mucus Hypersecretion through Activation of the Spleen Tyrosine Kinase–Epidermal Growth Factor Receptor–AKT/Extracellular Signal-Regulated Kinase 1/2 Signaling

Cited by 4 publications

References 98 publications

Dectin-1 Signaling Update: New Perspectives for Trained Immunity

Dectin-1 Signaling Update: New Perspectives for Trained Immunity

Human Airway Epithelium Responses to Invasive Fungal Infections: A Critical Partner in Innate Immunity

FoxA2 is a reliable marker for the diagnosis of yolk sac tumour postpubertal‐type

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