Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis

Abstract

Background: Chronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype-driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS. BODY: Thus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell-mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN-γ, TNF-α, IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion.

Conclusion: We believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

Keywords: chronic rhinosinusitis; cytokines; endotypes; immune response; mucin hypersecretion.

FIGURE 1

Regulation of mucin by Th1 cytokines associated with a type 1 immune response. (1) IFN‐γ can inhibit the release of Ca²⁺ from the endoplasmic reticulum through the JAK1/STAT1 signaling pathway, and can also block the binding of Sp1 to MUC5AC promoter region through the JAK1/STAT1 pathway, thus inhibiting the expression of MUC5AC gene. (2) IFN‐γ can directly inhibit MUC5AC expression through TGF‐β2 signaling pathway. (3) TNF‐α can significantly up‐regulate the expression of MUC5AC by hCLCA1., , (4, 5) TNF‐α induces the secretion of MUC5AC and MUC5B by activating two signaling pathways: PLC→DAG→PKC→NO→cGMP→PKG, ERK1/2→p38MAP→MSK1→cAMP. (6) TNF‐α can promote the expression of MUC5AC gene by inducing nuclear translocation of NF‐κB p65 subunit. (7) TNF‐α can impaired GR‐α nuclear translocation and inhibit the expression of NF‐κB p65, thus inhibiting the expression of MUC1 gene. (8) TNF‐α can induce MUC1 gene transcription by activating the MEK1/2/ERK1/Sp1 pathway., (9) TNF‐α can induce MUC2 gene transcription by activating the PKC/TK pathway.,

FIGURE 2

Regulation of mucin by Th2 cytokines associated with a type 2 immune response. (1, 2) IL‐5 can activate eosinophils through the activation of JAK2/STAT1/3/5/6 and MAPK2 signaling pathways,, which can cause the EGFR cascade reaction to induce MUC5AC gene transcription and protein synthesis., IL‐5 can indirectly promote secretion of MUC5AC and MUC5B by enhancing the proinflammatory effect of IL‐4 and IL‐13. (3) IL‐13 regulates the production of MUC5AC by enhancing the action of membrane protein TMEM16 A., , (4) IL‐13 enhances the action of C‐JUN to induce MUC5AC secretion by activating ERK1/2/AP‐1 signaling pathway. (5) IL‐13 promotes the production of MUC5AC by targeting miR‐141. (6, 7) IL‐4 can promote the production and secretion of MUC5AC and MUC5B by activating two signaling pathways of NF‐κB p65 and STAT6. IL‐4 receptor can enhance the affinity of IL‐13 to IL‐13 receptor α1, indirectly leading to MUC5AC secretion.. (8) IL‐10 induces Muc2 gene expression through activation of JAK2/STAT1/STAT3 signaling pathway., IL‐10 can indirectly induce MUC5AC secretion by enhancing the inflammatory process of IL‐13.

FIGURE 3

Regulation of mucin by Th17 cytokines associated with a type 3 immune response. (1) IL‐17 can induce MUC5AC secretion by activating the NF‐κB/EGFR/MAPK3/2 signaling pathway., , (2, 3) IL‐17 can indirectly upregulate the expression of MUC5AC gene by IL‐36‐mediated ERK1/2 or NF‐κB p65 signaling pathway., (4) IL‐17 can induce the expression of MUC5AC gene by activating Act1 signaling pathway. (5, 6) IL‐17 can directly or indirectly (via IL‐6) activate the ERK1/2 signaling pathway to induce MUC5B secretion., (7) IL‐22 can induce MUCI secretion by activating JAK1/STAT3 signaling pathway.,