Chemokine CCL19 and Its Receptors CCR7 and CCRL1 in Chronic Rhinosinusitis

Abstract

Background

CCL19 has been shown to predict disease severity in COVID-19 and treatment response in rheumatoid arthritis. CCL19 can exert both pro- and anti-inflammatory effects and is elevated in chronic rhinosinusitis (CRS). However, its role in CRS remains unknown. This study sought to determine the transcriptional changes in CCL19, its receptors, and associated cytokines and their association with disease severity in CRS.

Methods

A clinical database of control subjects and patients with CRS was examined. Lund-Kennedy, Lund-Mackay, Sinonasal Outcomes Test 22 (SNOT-22), and rhinosinusitis disability index (RSDI) scores were collected at enrollment. mRNA was extracted from sinonasal tissues and subjected to multiplex gene expression analysis. Gene transcript differences between patients with CRS and controls were compared and correlated with disease severity metrics. Immunohistochemical analyses of CCL19, CCR7, and CCRL1 were conducted to compare differences in protein expression between cohorts. A subgroup analysis was performed to compare transcriptional and protein expression difference between patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls.

Results

Thirty-eight subjects (control group, n=7; CRS group, n=31) were included in this study. CCRL1 (p=0.0093) and CCR7 (p=0.017) levels were significantly elevated in CRS compared to those in controls. CCL19 (p=0.038) and CCR7 (p=0.0097) levels were elevated in CRSwNP and CCRL1 was elevated in CRSsNP (p=0.0004). CCR7 expression was significantly elevated in sinonasal epithelial cells in CRSwNP (p=0.04). CCL19 expression was positively correlated with TNFA expression (p<0.0002). CCL19 and CCR7 expression was positively correlated with SNOT-22 and RSDI scores (p<0.05).

Conclusion

CCL19 and CCR7 may modulate TNF-α-driven pro-inflammatory signaling and contribute to increased disease severity in CRS. Mechanistic studies are required to further elucidate the role of CCRL1 in CRS.

Keywords:

• chronic rhinosinusitis with nasal polyps
• chemokines
• cytokines
• gene expression
• protein expression

Acknowledgments

The authors acknowledge the Biorepository and Molecular Pathology Shared Resource Core at the Huntsman Cancer Institute in Salt Lake City, UT, for tissue histology, mRNA isolation, and gene expression panel analysis. The authors also thank Emily K. Mechnick and Chelsea E. Pollard for their assistance in immunohistochemistry staining and imaging.

Disclosure

Abigail Pulsipher has a financial interest in GlycoMira Therapeutics. Jeremiah Alt and financial interests in GlycoMira Therapeutics, Inc. and is a consultant for GSK, Medtronic ENT, and OptiNose. None of these potential conflicts of interest are affiliated with this research. The authors report no other conflicts of interest in this work.

Additional information

Funding

This work was supported by grants from the Flight Attendant Medical Research Institute (CIA160008) and National Institute of Allergy and Infectious Diseases (R44 AI126987). The research reported in this publication was supported by the National Center for Advancing Translational Sciences under Award Numbers UM1TR004409 and 1K12TR004413. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.