tetano
Editor, Senior Moderator
Front Immunol
. 2026 Apr 17:17:1799580.
doi: 10.3389/fimmu.2026.1799580. eCollection 2026.
Respiratory epithelial cells as central mediators of immune crosstalk in SARS-CoV-2 infection
Xingjian Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Zhefen Mai[SUP] #[/SUP][SUP] 1 [/SUP], Lingbin Sun[SUP] 1 [/SUP], Liqiang Deng[SUP] 3 [/SUP], Moushen Tang[SUP] 4 [/SUP], Geng Li[SUP] 2 5 [/SUP], Xiaoyi Yang[SUP] 1 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces life-threatening acute lung injury (ALI) and disrupts immune homeostasis, however, the role of epithelial-immune cell crosstalk in driving this pathology remains incompletely elucidated. Respiratory epithelial cells (RECs) as the primary targets of SARS-CoV-2 via the ACE2 receptor, act as central mediators of immune crosstalk that balances antiviral defense and immunopathology in COVID-19. Beyond forming a physical barrier against pathogen invasion, RECs regulate bidirectional crosstalk with immune cells (including alveolar macrophages, dendritic cells, neutrophils, and lymphocytes) through multiple mechanisms, such as cytokine signaling, antigen presentation, PD-L1 checkpoint modulation, and renin-angiotensin-aldosterone system (RAAS) dysregulation. Under physiological conditions, these interactions promote viral clearance and epithelial repair; In contrast, dysregulation of such crosstalk leads to excessive inflammatory responses like cytokine storm and impaires tissue regeneration. Elucidating the molecular dynamics underlying REC-immune crosstalk is crucial for gaining insights into the development of targeted therapies (e.g., modulating cytokine signaling, restoring RAAS balance) to mitigate the severity of COVID-19. This review summarized recent findings to clarify how REC-mediated immune crosstalk dictates antiviral responses and pathological outcomes, thereby providing a theoretical basis for optimizing therapeutic strategies that strengthen antiviral immunity while minimizing immunopathology.
Keywords: COVID-19 pathogenesis; SARS-CoV-2; immune crosstalk; immunopathology; respiratory epithelial cells.
. 2026 Apr 17:17:1799580.
doi: 10.3389/fimmu.2026.1799580. eCollection 2026.
Respiratory epithelial cells as central mediators of immune crosstalk in SARS-CoV-2 infection
Xingjian Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Zhefen Mai[SUP] #[/SUP][SUP] 1 [/SUP], Lingbin Sun[SUP] 1 [/SUP], Liqiang Deng[SUP] 3 [/SUP], Moushen Tang[SUP] 4 [/SUP], Geng Li[SUP] 2 5 [/SUP], Xiaoyi Yang[SUP] 1 [/SUP]
Affiliations
- PMID: 42079584
- PMCID: PMC13132747
- DOI: 10.3389/fimmu.2026.1799580
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces life-threatening acute lung injury (ALI) and disrupts immune homeostasis, however, the role of epithelial-immune cell crosstalk in driving this pathology remains incompletely elucidated. Respiratory epithelial cells (RECs) as the primary targets of SARS-CoV-2 via the ACE2 receptor, act as central mediators of immune crosstalk that balances antiviral defense and immunopathology in COVID-19. Beyond forming a physical barrier against pathogen invasion, RECs regulate bidirectional crosstalk with immune cells (including alveolar macrophages, dendritic cells, neutrophils, and lymphocytes) through multiple mechanisms, such as cytokine signaling, antigen presentation, PD-L1 checkpoint modulation, and renin-angiotensin-aldosterone system (RAAS) dysregulation. Under physiological conditions, these interactions promote viral clearance and epithelial repair; In contrast, dysregulation of such crosstalk leads to excessive inflammatory responses like cytokine storm and impaires tissue regeneration. Elucidating the molecular dynamics underlying REC-immune crosstalk is crucial for gaining insights into the development of targeted therapies (e.g., modulating cytokine signaling, restoring RAAS balance) to mitigate the severity of COVID-19. This review summarized recent findings to clarify how REC-mediated immune crosstalk dictates antiviral responses and pathological outcomes, thereby providing a theoretical basis for optimizing therapeutic strategies that strengthen antiviral immunity while minimizing immunopathology.
Keywords: COVID-19 pathogenesis; SARS-CoV-2; immune crosstalk; immunopathology; respiratory epithelial cells.