Fc\u03b3RIII stimulation breaks the tolerance of human nasal epithelial cells to bacteria through cross-talk with TLR4

K Golebski,E.J De Groot,C.M Van Drunen,D Van Egmond,W Hoepel,W.J Fokkens,J.M Beekman,J Den Dunnen,G.D Amatngalim

doi:10.1038/s41385-018-0129-x

Abstract

The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosa or TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.

Highlights

The nasal cavity is constantly exposed to many different bacterial species, between which the immune system should discriminate and induce tolerance to commensals, while inducing protective inflammatory responses against invading pathogens.[1]
Human nasal epithelial cells are unresponsive to P. aeruginosa and LPS Bacterial species that reside in or invade the nasal cavity may either induce immune tolerance or pro-inflammatory responses
We set out to determine the immunological response of human nasal epithelial cells to pathogenic Gram-negative bacterium P. aeruginosa, which is capable of causing a broad range of infections of the respiratory airways and is the leading cause of morbidity and mortality in patients with cystic fibrosis.[11]

Summary

Introduction

The nasal cavity is constantly exposed to many different bacterial species, between which the immune system should discriminate and induce tolerance to commensals, while inducing protective inflammatory responses against invading pathogens.[1]. Since epithelial cells express bacteria-sensing PRRs, a potential explanation is that these cells require a ‘second signal’, in addition to the continuous exposure to bacterial antigens, to switch from a tolerogenic to an inflammatory phenotype. It is still unclear how nasal epithelial cells convert from immune tolerant to pro-inflammatory cells

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Conclusion