Galectin-10 and our expanding knowledge of olfactory cleft cytokines in olfactory dysfunction

Olfactory dysfunction (OD) is a common yet poorly understood sequelae of chronic rhinosinusitis (CRS). Up to 83% of patients with CRS experience some degree of loss of smell, yet the pathogenesis of this phenomenon has eluded researchers. In patients with type 2 disease, eosinophilic inflammation of the olfactory cleft mucosa and superior turbinate is highly associated with the onset and severity of OD. Consequently, olfactory cleft cytokines have become a topic of particular interest as researchers search to define specific endotypes and identify potential drug targets for patients with CRS and OD. In the current issue of the Annals of Allergy, Asthma & Immunology, we present one study that is the first to reveal a strong association between the type 2 inflammatory marker galectin-10 and OD in CRS.1Liu Z Hong J Huang X Wu D Olfactory cleft mucus galectin-10 predicts olfactory loss in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2023; 130: 317-324Abstract Full Text Full Text PDF Scopus (0) Google Scholar The impact of OD on patient quality of life should not be underestimated. OD has been found to significantly impair quality of life and is associated with increased medication use, depression, and decreased economic productivity.2Wu D Li Y Bleier BS Wei Y. Superior turbinate eosinophilia predicts olfactory decline in patients with chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 125 (304-310.e1)Abstract Full Text Full Text PDF Scopus (10) Google Scholar,3Mattos JL. Mechanisms and treatment of olfactory dysfunction in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 124: 307-308Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Previously thought to be a result of olfactory cleft blockage by nasal polyps,3Mattos JL. Mechanisms and treatment of olfactory dysfunction in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 124: 307-308Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar studies of superior turbinate biopsies and olfactory cleft mucosa have led to the emergence of direct eosinophilic inflammation of olfactory neuroepithelium as the leading hypothesis for OD in CRS. In addition, levels of tissue eosinophils also seem to be positively correlated with the degree of OD and have been proposed as a possible predictor of postoperative olfactory decline. This theory is also supported by the transient improvement in olfaction experienced by patients after endoscopic sinus surgery, ostensibly because of the removal of eosinophilic tissue.2Wu D Li Y Bleier BS Wei Y. Superior turbinate eosinophilia predicts olfactory decline in patients with chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 125 (304-310.e1)Abstract Full Text Full Text PDF Scopus (10) Google Scholar Although the exact mechanism leading to olfactory neurotoxicity is unknown, the implication of type 2 inflammation in OD presents an opportunity for targeted and individualized treatment. The mainstay treatment to date for OD in CRS involves control of sinonasal inflammation with the use of corticosteroids, either orally or topically. To avoid prolonged oral corticosteroids, topical steroids are usually used, but they may be limited in their ability to reach the olfactory cleft without the use of nebulizers or high-volume irrigation.3Mattos JL. Mechanisms and treatment of olfactory dysfunction in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 124: 307-308Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Olfactory training has been found to improve olfactory function in patients with posttraumatic, postinfectious, and idiopathic OD; however, further studies evaluating the role of olfactory training in treatment of CRS-related OD are needed.3Mattos JL. Mechanisms and treatment of olfactory dysfunction in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2020; 124: 307-308Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,4Whitcroft KL Hummel T. Clinical diagnosis and current management strategies for olfactory dysfunction: a review.JAMA Otolaryngol Head Neck Surg. 2019; 145: 846-853Crossref PubMed Scopus (73) Google Scholar More recently, biologics have emerged as a reliable treatment of CRS. Monoclonal antibodies targeting type 2 inflammatory mediators, such as interleukin (IL)-4, IL-5, IL-33, TSLP, and immunoglobulin E, have all been studied for the treatment of CRS with some trials revealing improvement in olfaction among some participants.5Laidlaw TM Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis.Ann Allergy Asthma Immunol. 2020; 124: 326-332Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The presence of both responders and nonresponders in these trials emphasizes the importance of responder analysis and the benefit of a wide array of biologics to choose from to individualize treatment. The authors of the present study bring up an important point; although eosinophilia is associated with OD in CRS, it is important to consider that eosinophil count is not the same as level of eosinophil activation. If new biomarkers and subsequent targeted therapies are to be studied and developed, we should ensure that the biomarkers play an active role in the disease process. Numerous olfactory cleft mucosal cytokines have been studied in the search for such biomarkers. Epithelial cells in the nasal mucosa have been found to perpetuate type 2 inflammation by secretion of cytokines including IL-25, IL-33, and TSLP, promoting differentiation of TH2 cells and activation of type 2 innate lymphoid cells.6Ordovas-Montanes J Dwyer DF Nyquist SK Buchheit KM Vukovic M Deb C et al.Allergic inflammatory memory in human respiratory epithelial progenitor cells.Nature. 2018; 560: 649-654Crossref PubMed Scopus (249) Google Scholar In addition, further studies into olfactory cell types have identified chemosensory cells and microvillus cells as major contributors to IL-25 release, mediating IL-5 and IL-3 secretion.7Kohanski MA Workman AD Patel NN Hung LY Shtraks JP Chen B et al.Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2018; 142 (460-469.e7)Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar With such a vast and expanding array of measurable inflammatory cytokines in olfactory cleft mucous, some studies have attempted to link CRS with OD to specific inflammatory endotypes.8Smith TL Schlosser RJ Soler ZM Mace JC Mattos JL Ramakrishnan VR et al.Olfactory cleft mucus inflammatory proteins in CRS: a case-control study.Int Forum Allergy Rhinol. 2021; 11: 1321-1335Crossref PubMed Scopus (11) Google Scholar Further expansion of the library of type 2 inflammatory markers associated with OD will be invaluable as we move toward personalized therapeutic options in the treatment of OD in CRS. Charcot-Leyden crystal protein, also known as galectin-10, has been associated with other eosinophilic diseases, such as asthma and allergic rhinitis, and has even been proposed as an accurate alternative to sputum eosinophilia measures in the diagnosis of asthma.9Nyenhuis SM Alumkal P Du J Maybruck BT Vinicky M Ackerman SJ. Charcot-Leyden crystal protein/galectin-10 is a surrogate biomarker of eosinophilic airway inflammation in asthma.Biomark Med. 2019; 13: 715-724Crossref PubMed Scopus (25) Google Scholar,10Chua JC Douglass JA Gillman A O'Hehir RE Meeusen EN Galectin-10, a potential biomarker of eosinophilic airway inflammation.PLoS One. 2012; 7: e42549Crossref PubMed Scopus (46) Google Scholar A hallmark of eosinophilic death, its association with type 2 inflammation has been well-established. Preclinical research has even revealed that crystalline galectin-10 (the activated structure of galectin-10) can be targeted and dissolved by anti–galectin-10 antibodies in vitro, supporting the idea that galectin-10 is a targetable biomarker.11Persson EK Verstraete K Heyndrickx I Gevaert E Aegerter H Percier J-M et al.Protein crystallization promotes type 2 immunity and is reversible by antibody treatment.Science. 2019; 364: eaaw4295Crossref PubMed Scopus (158) Google Scholar The authors of the present study are the first to reveal that galectin-10 is positively correlated with onset and severity of OD in CRS and provide evidence that mucus galectin-10 levels may be useful in predicting OD in patients with CRS. However, its mechanistic role in the type 2 inflammation pathway is still unknown and is certainly worthy of future study. As our knowledge of the pathobiology of OD in CRS expands, the search for targeted therapies becomes the focus of great effort by researchers. Highlighted in this review is the success of the authors in providing further evidence that galectin-10 is highly associated with eosinophilia. More importantly, they are the first to reveal an association between galectin-10 and OD in CRS and that it may be a useful biomarker for predicting OD in patients with CRS. The authors suggest that galectin-10 may prove to be a useful target for future drug therapies, and the literature seems to support this idea. Further studies should focus on the underlying mechanisms of galectin-10 and type 2 inflammation. The pathogenesis of CRS and OD seems to be intertwined, and elucidation of the mechanisms behind OD in CRS may deepen our understanding of CRS as a whole. Olfactory cleft mucus galectin-10 predicts olfactory loss in chronic rhinosinusitisAnnals of Allergy, Asthma & ImmunologyVol. 130Issue 3PreviewEosinophils have been reported to be involved in the pathogenesis of olfactory fluctuation in chronic rhinosinusitis (CRS). Galectin-10 is more frequently associated with type 2 inflammation and potentially a sign of intense eosinophil activation. Full-Text PDF