Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin

Abstract

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide. It is a heterogeneous disease, and geographical or ethnic differences in inflammatory pattern in nasal mucosa are major issues. Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher nasal polyp (NP) recurrence rate after surgery. The prevalence of eosinophilic CRS (ECRS) is increasing in Asian countries within the last 2 decades, and this trend appears to be occurring across the world. International consensus criteria for ECRS are required for the accurate understanding of disease pathology and precision medicine. In a multicenter large-scale epidemiological survey, the "Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study," ECRS was definitively defined when the eosinophil count in nasal mucosa is greater than or equal to 70 eosinophils/hpf (magnification, ×400), and this study proposed an algorithm that classifies CRS into 4 groups according to disease severity. The main therapeutic goal with ECRS is to eliminate or diminish the bulk of NP tissue. NPs are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses, and type 2 inflammation plays a critical role in NP development in patients with ECRS. An imbalance between protease and endogenous protease inhibitors might play a pivotal role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells in NPs, showing a tryptase+, chymase- phenotype, may also enhance type 2 inflammation. Intense edema and reduced fibrosis are important histological features of eosinophilic NPs. Mucosal edema mainly consists of exuded plasma protein, and excessive fibrin deposition would be expected to contribute to the retention of proteins from capillaries and thereby perpetuate mucosal edema that may play an etiological role in NPs. Upregulation of the coagulation cascade and downregulation of fibrinolysis strongly induce abnormal fibrin deposition in nasal mucosa, and type 2 inflammation plays a central role in the imbalance of coagulation and fibrinolysis.

Keywords: Chronic rhinosinusitis; coagulation cascade; fibrin; fibrinolysis; mast cell; nasal polyps; tissue plasminogen activator; tryptase.

FIG 1.

JESREC score criteria for the diagnosis of ECRS (left). Diagnostic algorithm for ECRS severity. Patients with CRS would be classified into 4 groups by JESREC score: blood eosinophilia, ethmoid dominant shadow in CT, and comorbidity (bronchial asthma, aspirin/NSAID intolerance). The moderate/severe ECRS groups showed type 2–dominant inflammation, and non-ECRS/mild ECRS groups showed type 1/type 3 mixed inflammation (right). CT, Computed tomography; NSAID, nonsteroidal anti-inflammatory drug.

FIG 2.

Establishment of type 2 inflammation in ECRS. Innate response to exogeneous proteases from allergens, such as pollen, mite, fungi, and microorganisms, can induce the epithelial-derived cytokines IL-33, IL-25, and TSLP, which drive the activation of ILC2s to release type 2 cytokines in an antigen-independent manner. An imbalance between allergen proteases and EPIs might play a role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells, showing a tryptase+, chymase− phenotype (MC-T), enhance type 2 inflammation. Cystatin SN enhances TSLP expression, and that stimulation with TSLP or IL-33 increased cystatin SN expression in nasal epithelial cells. Cystatin SN plays a role in eosinophilic inflammation in ECRS through inducing CCL11 and periostin expression in NPs fibroblast. Downregulation of the tPA/LRP-1 pathway reduces NO production. NO contributes to the local host defense through regulation of ciliary motility. mDC, Myeloid dendritic cell.

FIG 3.

Hypothetical models to explain the role of coagulation and fibrinolysis in excessive fibrin deposition and low fibrosis in eosinophilic NPs. L-plastin might be involved in the translocation of TF to the eosinophil cell surface, which in turn initiates coagulation cascade and induces subsequent fibrin deposition in nasal mucosa. Increased expression of TAFI downregulates plasmin activity. Type 2 inflammation leads to the recruitment of M2 macrophages and the subsequent production of FXIII-A, which induces fibrin cross-linking. Type 2 cytokine and DNA methylation attenuates tPA expression, causing impaired plasmin generation, which in turn decreased fibrinolysis. Nattokinase shrinks NPs through strong fibrinolytic activity. SCFAs mediate tPA expression in nasal epithelial cells.