Protein S protects against allergic bronchial asthma by modulating Th1/Th2 balance

Abstract

Background Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti‐inflammatory, and anti‐apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. Methods To address this question here we compared the development of allergen‐associated bronchial asthma between wild type and protein S‐overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. Results The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild‐type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2‐mediated lung inflammation in allergic wild‐type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL‐12, tumor necrosis factor‐α) from dendritic cells. Conclusions These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.

Advances and highlights in asthma in 2021

“…Protein S is a glycoprotein with anticoagulant, anti‐inflammatory and anti‐apoptotic properties. Protein S induces the release of IL‐12 and TNF‐α by bronchial mDCs, thus preventing Th2 polarization and decreasing AHR 41 …”

Advances and recent developments in asthma in 2020

“…A Th1/Th2 imbalance is commonly seen in allergic asthma, and it is shifted back toward Th1 by protein S. Protein S, an anticoagulant, anti‐inflammatory, and anti‐apoptotic glycoprotein, is associated with a reduction of AHR, lung tissue inflammatory cell infiltration, Th2 cytokines in the lung, and IgE levels. Asayama et al showed that it could inhibit allergic asthma by upregulating the type 1 cytokines TNF‐α and IL‐12 while downregulating IL‐5 + Th2 cells 61 . A downregulation of Th2 cells is also achieved by intraperitoneal injection of cysteamine, along with IL17 + Th17 and IL13 + IL17 + Th2/Th17 cells, thus effectively inhibiting AHR in an allergic mouse model upon retreatment with the allergen 62 .…”

Role of liver‑X‑receptors in airway remodeling in mice with chronic allergic asthma

“…However, to the best An important feature of allergic asthma is the increase in IgE levels in the serum. IgE-mediated type I allergy is the primary mechanism of the asthma response and leads to airway hyperresponsiveness (24), particularly when asthmatic patients are exposed to allergens. Allergens are captured by antigen-presenting cells and are presented to T lymphocytes, which is a process that requires a suitable Th2 cytokine environment to enable the B-cell type conversion to a type that produces IgE (25)(26)(27).…”