Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of group 2 innate lymphoid cells (ILC2s). Although a member of TNF superfamily (TNFSF), TNFSF15, is known to induce production of type 2 cytokines in ILC2s, the role of other TNFSFs in ILC2s and the importance of TNFSFs in ILC2-mediated inflammation in CRSwNP have not been elucidated.
We investigated the presence of TNFSFs in nasal polyps (NPs) by microarray, real-time RT-PCR and Luminex, and the expression of TNFSF receptors (TNFRSFs) in human ILC2s by RNA-sequencing and flow cytometry. Purified human ILC2s were stimulated with recombinant TNFSFs and thymic stromal lymphopoietin (TSLP) and the production of type 2 cytokines from ILC2s was evaluated by Luminex.
Although TNFSF15 was not elevated, mRNAs for TNFSF6, TNFSF11, TNFSF14, and TNFSF18 were significantly elevated in NPs compared to normal uncinate tissue and mRNAs for their receptors, TNFRSF6, TNFRSF11A, TNFRSF14, and TNFRSF18 were detected in human ILC2s. Among identified TNFSFs, only recombinant TNFSF11 and agonistic anti-TNFRSF11A antibody were able to induce the production of IL-13 in blood ILC2s. We confirmed that TNFSF11 protein was significantly elevated in NP tissue and TNFRSF11A protein was detected on ILC2s from blood and NPs. The presence of mRNA (n=60) and protein (n=96) for TNFSF11 significantly correlated with IL-13 in sinonasal tissue. Interestingly, TSLP enhanced the TNFSF11-mediated production of IL-13 in blood ILC2s (5.0-fold, p<0.01, n=7).
TNFSF11 together with TSLP may play an important role in the ILC2-mediated type 2 inflammation seen in patients with CRSwNP.