Cystatin SN—more than a type 2 immunity marker

We read with great interest the original article by Nocera et al1Nocera A.L. Mueller S.K. Workman A.D. Wu D. McDonnell K. Sadow P.M. et al.Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.J Allergy Clin Immunol. 2022; 150: 872-881Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar that was published in the Journal of Allergy and Clinical Immunology and titled “Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.” This research sheds light on the mechanism of cystatin SN (encoded by the gene cystatin SN [CST1]) regulation of type 2 (T2) inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). Previously, our laboratory2Yan B. Lou H. Wang Y. Li Y. Meng Y. Qi S. et al.Epithelium-derived cystatin SN enhances eosinophil activation and infiltration through IL-5 in patients with chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2019; 144: 455-469Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar found that cystatin SN can recruit and activate eosinophils through IL-5, and Kato et al3Kato Y. Takabayashi T. Sakashita M. Imoto Y. Tokunaga T. Ninomiya T. et al.Expression and functional analysis of CST1 in intractable nasal polyps.Am J Respir Cell Mol Biol. 2018; 59: 448-457Crossref PubMed Scopus (47) Google Scholar found that eotaxin and periostin are also involved. In their study, Nocera et al1Nocera A.L. Mueller S.K. Workman A.D. Wu D. McDonnell K. Sadow P.M. et al.Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.J Allergy Clin Immunol. 2022; 150: 872-881Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar found that exposure to recombinant human cystatin SN can induce a variety of T2 cytokines from healthy murine mucosa in a time-dependent manner and that P-glycoprotein (P-gp) is involved in this process. P-gp upregulation by cystatin SN may explain the increase in IL-5 level caused by cystatin SN, as P-gp can directly increase IL-5 secretion through posttranslational regulation.4Bleier B.S. Singleton A. Nocera A.L. Kocharyan A. Petkova V. Han X. P-glycoprotein regulates Staphylococcus aureus enterotoxin B-stimulated interleukin-5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants.Int Forum Allergy Rhinol. 2016; 6: 169-177Crossref PubMed Scopus (18) Google Scholar However, this raises the question of how cystatin SN regulates P-gp in detail. Nocera et al1Nocera A.L. Mueller S.K. Workman A.D. Wu D. McDonnell K. Sadow P.M. et al.Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.J Allergy Clin Immunol. 2022; 150: 872-881Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar found that cystatin SN is upregulated in exosomes from nasal polyps compared with in those from normal mucosa. This finding may shed light on exploration of cystatin SN in CRSwNP. Our previous results using in situ hybridization showed that CST1 is restricted to epithelial cells.2Yan B. Lou H. Wang Y. Li Y. Meng Y. Qi S. et al.Epithelium-derived cystatin SN enhances eosinophil activation and infiltration through IL-5 in patients with chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2019; 144: 455-469Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Cystatin SN is a secretory protein, so it can function in the extracellular matrix as a cysteine protease inhibitor or just as a protein irrelevant to its inhibitory activity. However, it is also possible that cystatin SN can be transferred to other cells (eg, T cells) through exosomes. Indeed, many T2 cytokines induced by cystatin SN are from immune cells, not from epithelial cells. Furthermore, according to the Human Protein Atlas public database (https://www.proteinatlas.org), P-gp localizes in plenty of immune cells, although the data from immunohistochemistry staining in polyp tissue have focused on epithelial cells.4Bleier B.S. Singleton A. Nocera A.L. Kocharyan A. Petkova V. Han X. P-glycoprotein regulates Staphylococcus aureus enterotoxin B-stimulated interleukin-5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants.Int Forum Allergy Rhinol. 2016; 6: 169-177Crossref PubMed Scopus (18) Google Scholar Here, we suggest that exosomes can serve as carriers for delivery of cystatin SN from epithelial cells to immune cells to regulate molecules such as P-gp; however, this hypothesis should be confirmed in a well-designed experiment. Previously, Nocera et al5Nocera A.L. Miyake M.M. Seifert P. Han X. Bleier B.S. Exosomes mediate interepithelial transfer of functional P-glycoprotein in chronic rhinosinusitis with nasal polyps.Laryngoscope. 2017; 127: E295-E300Crossref PubMed Scopus (33) Google Scholar showed that autologous exosomes can transfer functional P-gp to epithelial cells, and the method described may serve as a working model. Future studies should emphasize the communication between cells, as cystatin SN may serve as a mediator in this cross talk (Fig 1). Cystatin SN serves as a novel and promising marker of T2 inflammation in upper airway diseases. The evaluation is based on the total amount of cystatin SN. In the study of interest, Nocera et al1Nocera A.L. Mueller S.K. Workman A.D. Wu D. McDonnell K. Sadow P.M. et al.Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.J Allergy Clin Immunol. 2022; 150: 872-881Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar found multiple posttranslational modifications of cystatin SN in samples from patients with CRSwNP but not in samples of normal mucosa. Whether cystatin SN modification can reflect disease severity needs further exploration. In conclusion, cystatin SN is more than a novel and promising marker of T2 inflammation, with its level in nasal secretion or exosomes reflecting disease severity. Further, a growing number of studies are revealing its role in regulating T2 inflammation. Detailing the role of cystatin SN regulatory and signaling pathways in T2 immunity remains an ongoing effort. Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitisJournal of Allergy and Clinical ImmunologyVol. 150Issue 4PreviewCystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 151Issue 1PreviewI read with great interest the comment by Yan et al1 on the article “Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.”2 In their comment, Yan et al1 hypothesize that cystatin SN, an epithelial-derived secreted protein, may be transferred to immune cells (eg, T cells) via exosomes, where it could act to promote canonic type 2 (T2) cytokine secretion under the influence of P-glycoprotein (P-gp). Broadly speaking, I find this mechanism plausible and consistent with our laboratory’s findings that sinonasal mucosa–derived extracellular vesicles (eg, exosomes) harbor an array of membrane-bound and secretory proteins (eg, P-gp3 and cystatins, respectively), which may be donated to adjacent cells. Full-Text PDF