Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice

Abstract

Background: Secretoglobin (SCGB) 3A2, a novel, lung-enriched, cytokine-like, secreted protein of small molecular weight, was demonstrated to exhibit various biological functions including anti-inflammatory, antifibrotic and growth-factor activities. Anti-inflammatory activity was uncovered using the ovalbumin-induced allergic airway inflammation model. However, further validation of this activity using knockout mice in a different allergic inflammation model is necessary in order to establish the antiallergic inflammatory role for this protein. Methods:Scgb3a2-null (Scgb3a2^-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. Results: Exacerbated inflammation was found in the airway of Scgb3a2^-/- mice subjected to house dust mite (HDM)-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2^-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2^-/- mice than wild-type mice or saline-treated Scgb3a2^-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. Conclusions: These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted.

A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death

“…This work takes a significant step forward to elucidate and describe a new pathway impacted by SCGB3A2 functioning as a tumor suppressor protein. Previously we showed that SCGB3A2 functions as an anti-inflammatory and anti-fibrotic agent in the lung ( Cai and Kimura, 2015 ; Cai et al, 2014 ; Chiba et al, 2006 ; Kido et al, 2014 ; Kurotani et al, 2011 ; Yoneda et al, 2016 ). Because SCGB3A2 is mainly secreted by club cells in lung airways, it is reasonable to assume that a primary function of SCGB3A2 is to protect the hosts from pathogens and pathogen-associated molecular patterns such as LPS.…”

“…A cytokine-like small secreted protein, SCGB3A2 (secretoglobin 3A2, also known as UGRP1 and HIN-2), was previously identified that is abundantly and specifically expressed in non-ciliated airway epithelial (club) cells of the trachea, bronchus, and bronchioles ( Niimi et al, 2001 ) and revealing that SCGB3A2 functions to suppress lung inflammation and fibrosis ( Cai and Kimura, 2015 ; Cai et al, 2014 ; Chiba et al, 2006 ; Kido et al, 2014 ; Kurotani et al, 2011 ; Yoneda et al, 2016 ). Although specific expression of SCGB3A2 in lung epithelial cells and its role in inflammation may imply a possible important function for SCGB3A2 in the clearance of pathogens, its role in host defense, if any, has not been studied.…”

Recent Advances in Experimental Allergy

“…Of particular interest is that the mRNA levels of Ccr4 and Ccl17 levels were higher in HDM-treated lungs of Scgb3a2 KD animals when compared to saline-treated KD animals. This suggests a regulatory role of SCGB 3A2 in the CCR4-CCL17 pathway and confirms its anti-inflammatory mode of action [24]. …”

“…SCGB 3A2 is a small molecular weight cytokine-like, secreted protein, which was recently shown to be enriched in the murine lung and possessing a variety of pharmacological activities [23]. Yoneda et al [24] sought to validate the previously published anti-inflammatory actions of SCGB 3A2 in an HDM-induced allergic airway inflammation model using Scgb3a2 KO mice. More severe airway inflammation was observed in Scgb3a2 KO mice sensitized/challenged with HDM allergens.…”

Spatiotemporal Expression of Three Secretoglobin Proteins, SCGB1A1, SCGB3A1, and SCGB3A2, in Mouse Airway Epithelia

“…4,[7][8][9][10] SCGB3A2, also called UGRP1, 6 appears to share activities similar to those of SCGB1A1. It was demonstrated to exhibit antiinflammatory, [11][12][13][14][15] growth factor, 16,17 and antifibrotic activities. [17][18][19][20] SCGB3A2 also serves as a marker for lung adenocarcinomas.…”