The advance on pathophysiological mechanisms of type 2 chronic rhinosinusitis with nasal polyposis

Abstract

Purpose: This review aims to explore the pathophysiological mechanisms and emerging therapies for type 2 chronic rhinosinusitis with nasal polyps (CRSwNP), driven primarily by type 2 inflammation.

Search methods: A comprehensive search of relevant literature was performed in databases including PubMed, Web of Science, and Scopus, using keywords such as "chronic rhinosinusitis with nasal polyps," "type 2 inflammation," "Th2 cells," "ILC2s," "epithelial barrier dysfunction," and "biologics". The search was limited to articles published from January 2010 to February 2025.

Search results: A total of 200 articles were initially retrieved. After screening based on relevance and quality, 163 articles were selected for this review. These included 109 basic research papers, 30 clinical studies, and 24 review articles.

Conclusions: Type 2 CRSwNP pathogenesis involves Th2/ILC2-IL-4/IL-13 synergy, driving eosinophilic inflammation and tissue remodeling via a self-amplifying loop. Programmed cell death protein 1 and programmed death-ligand 1 dysregulation intensifies Th2 responses. Epithelial barrier defects (via disrupted junctions and ciliary defects) and epithelial-mesenchymal transition facilitate pathogen invasion and stromal changes. M2 macrophages amplify inflammation via CCL-24 and Staphylococcus aureus synergy, sustaining biofilm persistence. Targeted biologics-dupilumab (IL-4Rα inhibitor) reduces polyp burden and restores smell, while mepolizumab (anti-IL-5) and omalizumab (anti-IgE) address specific endotypes. Despite therapeutic advances, biologics require real-world validation for long-term safety and cost-effectiveness.

Keywords: biologics; chronic rhinosinusitis with nasal polyposis (CRSwNP); epithelial barrier dysfunction; type 2 T helper cells (Th2); type 2 innate lymphoid cells (ILC2s).

Figure 1

Following injury or stimulation, nasal mucosal epithelial cells release epithelial-derived alarmins such as IL-25, IL-33, and TSLP, which activate ILC2s to produce IL-4. IL-4 plays a critical role in early-phase Th2 inflammation by activating the STAT6 pathway and upregulating the transcription factor GATA3, which, in turn, amplifies the transcription of IL-4, IL-5, and IL-13 (34). IL-13 promotes the migration of activated dendritic cells from nasal polyps to draining lymph nodes, where they present antigens and prime naive CD4T cells to differentiate into Th2 cells (35). These Th2 cells secrete IL-4, IL-5, and IL-13, driving IgE production, eosinophil activation/recruitment, and tissue remodeling (29, 30). The profibrotic activities of IL-4 and IL-13 are predominantly mediated through TGF-β-dependent mechanisms (36). Binding of these cytokines to their cognate receptors triggers transmembrane JAK kinase phosphorylation cascades, promoting STAT protein homodimerization and nuclear translocation, thereby amplifying autocrine IL-4/IL-13 signaling and downstream gene expression (38, 39). Concurrently, TGF-β forms profibrotic transcriptional regulatory units via SMAD signaling complexes (40). These two pathways exhibit functional synergy in the nuclear compartment, ultimately leading to aberrant fibroblast proliferation, myofibroblast differentiation, and pathological ECM deposition, exacerbating tissue remodeling.

Figure 2

Monocytes differentiate into M0 macrophages, which further polarize into M1 and M2 macrophages. M1 macrophages drive proinflammatory responses and Th1/antipathogen immunity by secreting TNF-α, IL-6, and IL-12 (82). MIF enhances M2 macrophage polarization and promotes CCL-24 secretion by M2 macrophages (96, 97). M2 macrophages contribute to type 2 inflammation through multiple mechanisms: CCL-24 mediates eosinophil recruitment (98), MMPs participate in extracellular matrix deposition (104), VEGF promotes hyperplasia of nasal mucosal epithelial cells and interstitial edema (103), while TGF-β and IL-10 drive nasal mucosal epithelial damage and remodeling (86). Collectively, these processes synergistically amplify type 2 inflammatory responses.