PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Abstract

Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

Advances and highlights in asthma in 2021

“…Genetic variants in PAG1 were associated with asthma risk. PAG1 deficiency increased Th2 differentiation and favoured allergic sensitization 39 . Acid sphingomyelinase, a key regulator of sphingosine‐1‐phosphate pathway, promotes Th1 immunity in the airways.…”

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

“…Specifically, ILC2s secreted less type 2 cytokines in the early stage of influenza-induced acute exacerbation, and became the main source after virus clearance, while T cells showed increased production of IL-4 and IL-5 in the early stage [ 99 ]. It is easy to sensitize and aggravate the degree of asthma by promoting ILC2s amplification and Th2 differentiation [ 100 ]. Blocking T cell activation and Treg inhibition and promoting the increase of ILC2s could lead to severe Th2 immune response and airway inflammation [ 17 ].…”

Bone Marrow Mesenchymal Stem Cells Expanded Inside the Nichoid Micro-Scaffold: a Focus on Anti-Inflammatory Response

“…Finally, PAG1, which affected immune receptor signaling in T and B cells, was up-regulated and limited the inflammation effect. Indeed, Ullah et al demonstrated that the PAG1 deficiency predisposed toward allergic sensitization and airways inflammation [ 62 ]. The results of gene up-regulation in BM-MSCs expanded inside the Nichoid, in agreement with the above-reported studies, suggest the improvement of the cells’ anti-inflammatory effects, possibly potentiating the therapeutic outcome of BM-MSCs.…”