NEDD4 like E3 ubiquitin protein ligase-mediated ubiquitination and degradation of dipeptidyl peptidase 4 restrains Th2-linked inflammation in allergic rhinitis

Allergic rhinitis (AR) is a chronic inflammatory disorder characterized by type 2 T helper (Th2) cell-dominant immune responses. NEDD4 like E3 ubiquitin protein Ligase (NEDD4L) plays a role in regulating T cell activation and Th cell differentiation. Dipeptidyl Peptidase 4 (DPP4) is involved in Th2 inflammatory responses in AR. In this study, NEDD4L was found to be downregulated in peripheral blood CD4⁺-enriched T cells from AR patients. In a BALB/c mouse model of AR, established by intraperitoneal sensitization with 25 μg ovalbumin (OVA) followed by intranasal challenge with 500 μg OVA, NEDD4L expression was also reduced in splenic T cells enriched in CD4⁺ populations. T cell-specific overexpression of NEDD4L, achieved via tail vein injection of lentivirus carrying the CD3δ promoter, significantly alleviated AR symptoms, as shown by reduced sneezing and nose-wiping frequency, and decreased serum levels of OVA-specific immunoglobulin E (IgE) and histamine. Moreover, NEDD4L overexpression attenuated nasal mucosal thickening, inflammatory cell infiltration, and goblet cell hyperplasia. In vitro, lentiviral-mediated NEDD4L overexpression in T cells, enriched in CD4⁺ populations, is associated with suppression of Th2-linked inflammation, as indicated by decreased GATA-binding protein 3 (GATA-3) and JunB proto-oncogene (JunB) protein levels, reduced secretion of Th2 cytokines, and a lower proportion of CD4⁺IL-4⁺ cells. Mechanistically, NEDD4L ubiquitinates DPP4 at the K583 site to promote its degradation, and DPP4 overexpression reversed the anti-inflammatory effects of NEDD4L. Collectively, NEDD4L is consistent with acting as a negative regulator of Th2-linked inflammation, potentially via ubiquitination-mediated degradation of DPP4.