REVIEW article
Front. Immunol.
Sec. Mucosal Immunity
This article is part of the Research TopicImmunology in Oral DiseasesView all 6 articles
Molecular Mechanisms of Neutrophil Regulatory Network in Anti-Candida Infection
Provisionally accepted
- 1Kunming Medical University, Kunming, China
- 2Zhejiang University School of Medicine, Hangzhou, China
- 3University of Pennsylvania School of Dental Medicine, Philadelphia, United States
- 4University of Pennsylvania, Philadelphia, United States
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Candida albicans resides as a commensal within the oral mucosa but becomes pathogenic when epithelial or immune equilibrium collapses. Neutrophils constitute the dominant effector population controlling this transition, integrating pathogen-and host-derived cues into a coordinated antimicrobial program. Fungal β-glucan recognition through Dectin-1 and complement receptor 3 (CR3) activates spleen tyrosine kinase (SYK)–phosphoinositide 3-kinase (PI3K)– extracellular signal-regulated kinase (ERK) pathways and drives microtubule-associated protein 1 light chain 3B-II (LC3B-II) accumulation and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome assembly, thereby coupling phagocytosis with oxidative burst and neutrophil extracellular trap (NET) formation. Caspase recruitment domain-containing protein 9 (CARD9)-dependent interleukin (IL)-17 and tumor necrosis factor-α (TNF-α) circuits sustain chemokine (C-X-C motif) ligand 1/2 (CXCL1/2)-directed neutrophil recruitment and granulocyte colony-stimulating factor (G-CSF)-mediated granulopoiesis, while tissue matrix components determine site-specific antigen handling and NETosis thresholds. Hypha-restricted peptide toxin Candidalysin links epithelial injury to NLRP3 activation and release of IL-1β, IL-6, and G-CSF, establishing an oropharyngeal candidiasis (OPC)-specific neutrophil regulatory loop critical for pathogen clearance but also for mucosal inflammation. Conversely, fungal morphogenesis, biofilm organization, and metabolic rewiring dampen reactive oxygen species (ROS) generation and promote immune tolerance and drug resistance. Clinically, G-/granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvants and G-CSF-mobilized granulocyte transfusion offer context-dependent benefits yet pose toxicity risks, underscoring the need for precise intervention in neutrophil activation. Advances in single-cell and spatial multi-omics approaches are uncovering the metabolic and functional heterogeneity of neutrophils within mucosal environments, providing mechanistic insight for targeted immunomodulation.
Keywords: Neutrophil, oral candidiasis, Candida albicans, Neutrophil extracellular trap (NET), Immune Regulatory Networks
Received: 30 Sep 2025; Accepted: 31 Oct 2025.
Copyright: © 2025 Xu, Renyi, Li, Yu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Chider Chen, chenc10@upenn.edu
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