The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.

Keywords: CRSwNP; biologic; chronic rhinosinusitis with nasal polyps; cytokine; interleukin-13; interleukin-4; interleukin-4 receptor; type 2 inflammation.

Figure 1

Type 2 inflammatory pathways in CRSwNP. (A) Type 2 inflammatory pathways at the nasal epithelium and thymus; (B) Th2 cell differentiation and activation. CRSwNP, chronic rhinosinusitis with nasal polyps; EMT, epithelial-to-mesenchymal transition; FCεRI, immunoglobulin E receptor; IgE, immunoglobulin E; IL, interleukin; iNOS, inducible nitric oxide synthase; OX40L, OX40 ligand; MHC, major histocompatibility complex; TCR, T cell receptor; Th, T helper; TSLP, thymic stromal lymphopoietin.

Figure 2

Biologics targeting type 2 inflammation in CRSwNP. βc, beta chain; γc, gamma chain; ADCC, antibody-dependent cellular cytotoxicity; CCL17, C–C motif chemokine ligand 17; IFNγ, interferon gamma; IgE, immunoglobulin E; IL, interleukin; ILC, innate lymphoid cell; MCP-4, monocyte chemoattractant protein-4; R, receptor; Th, T helper; TSLP, thymic stromal lymphopoietin.