Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Abstract

Purpose Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms. Methods In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms. Results We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis. Conclusion Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.

HDM induce airway epithelial cell ferroptosis and promote inflammation by activating ferritinophagy in asthma

“…Additionally, we found that NCOA4 knockdown alleviated HDM‐induced free iron level increases and reduced the cell death rate (Figure 7E,F). A recent study demonstrated that HDM activated autophagy in airway epithelial cells 30 . In agreement with this observation, HDM exposure increased the expression of the autophagy‐related protein LC3 in HBE cells (Figure 7G).…”

“…A recent study demonstrated that HDM activated autophagy in airway epithelial cells. 30 In agreement with this observation, HDM exposure increased the expression of the autophagy-related protein LC3 in HBE cells (Figure 7G). FTH accumulation was also enhanced when autophagy was inhibited by ATG5 and P62 siRNA transfection and by treatment with the autophagy inhibitor chloroquine (CQ) (Figure 7H,M and Figure S3B).…”

Progranulin deficiency suppresses allergic asthma and enhances efferocytosis via PPAR‐γ/MFG‐E8 regulation in macrophages

“…In this study, we found that OVA‐induced airway inflammation was significantly suppressed in PGRN‐deficient mice, consistent with a proinflammatory role but not with the anti‐inflammatory role of PGRN in allergic asthma. 22 , 23 , 24 Therefore, in our study, we used PGRN deficient mice to investigate the role and possible mechanisms for PGRN regulation of the development of allergic inflammation.…”

Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)

“…GRN -deficient HaCaT cells display reduced LC3-II levels, and inhibition of the Wnt/β-catenin signalling pathway through IWP-2 treatment elevates the levels of LC3-II affected by GRN -deficiency ( Tian et al, 2016 ). Under other inflammatory-based conditions like asthma, recombinant GRN delivered nasally ameliorates indicators of impaired autophagy such as lowering protein levels of LC3, BECN1, and the number of autophagosomes in mice ( Liu et al, 2021 ). Liu et al (2021) show and postulate that these autophagic indicators may be regulated by GRN via high mobility group box 1 (HMGB1), a protein that is upstream of the MAPK/ERK pathway and is suppressed by GRN, which negatively modulates autophagy ( Figure 2 ).…”

“…Under other inflammatory-based conditions like asthma, recombinant GRN delivered nasally ameliorates indicators of impaired autophagy such as lowering protein levels of LC3, BECN1, and the number of autophagosomes in mice ( Liu et al, 2021 ). Liu et al (2021) show and postulate that these autophagic indicators may be regulated by GRN via high mobility group box 1 (HMGB1), a protein that is upstream of the MAPK/ERK pathway and is suppressed by GRN, which negatively modulates autophagy ( Figure 2 ). As GRN is known to be a protective biomolecule in the context of several neurodegenerative diseases, GRN may be asserting its protective effect against excitotoxicity within the autolysosomal pathway despite being an extracellular protein ( Davis et al, 2021 ; Terryn et al, 2021 ).…”