Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis.

Ji Heui Kim,Go Eun Choi,Yong Ju Jang,Bong-Jae Lee,Seung-Hyo Lee,Seog Woon Kwon,Hun Sik Kim

doi:10.1038/srep27615

Abstract

Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS.

Highlights

Prostaglandin (PG) derived from arachidonic acid is produced in most tissues and organs and has various physiological effects, such as regulation of inflammation
To determine whether eosinophil apoptosis was primarily mediated by NK cells or a general capacity shared by other lymphocytes in peripheral blood mononuclear cells (PBMCs), a CD56-depleted lymphocyte population was used in the apoptosis experiments (Supplementary Fig. S2)
CD56-depleted lymphocytes exhibited a significant decrease in triggering eosinophil apoptosis, suggesting that the ability to induce eosinophil apoptosis is mostly confined to NK cells (Fig. 1b)

Summary

Introduction

Prostaglandin (PG) derived from arachidonic acid is produced in most tissues and organs and has various physiological effects, such as regulation of inflammation. PGDS expression is increased in nasal polyps (NPs) and positively correlates with eosinophilic inflammation[17]. The concentration of PGD2 is elevated in NPs and strongly correlates with the number of mast cells that mainly produce PGD2 and play crucial pathogenic roles in CRSwNP18. PGD2 may be an important contributing factor to eosinophilic inflammation of CRS. We speculated that the increased PGD2 level and decreased NK cell function observed in patients with CRS may be associated with eosinophilic inflammation in the sinonasal tissue and blood eosinophilia. We obtained evidence indicating that NK cell dysfunction is potentially linked to PGD2 dysregulation and eosinophilic inflammation in CRS

Methods

Results

Conclusion