Heat shock protein 70 is a positive regulator of airway inflammation and goblet cell hyperplasia in a mouse model of allergic airway inflammation

Abstract

Heat shock proteins (Hsps) are highly conserved molecular chaperones that are ubiquitously expressed in all species to aid the solubilization of misfolded proteins, protein degradation, and transport. Elevated levels of Hsp70 have been found in the sputum, serum, and bronchoalveolar lavage (BAL) fluid of asthma patients and are known to correlate with disease severity. However, the function of Hsp70 in allergic airway inflammation has remained largely unknown. This study aimed to determine the role of Hsp70 in airway inflammation and remodeling using a mouse model of allergic airway inflammation. WT and Hsp70 double-knockout (Hsp70.1/.3 ؊/؊) mice were sensitized and challenged intratracheally with Schistosoma mansoni soluble egg antigens (SEAs) to induce robust Th2 responses and airway inflammation in the lungs. The lack of Hsp70 resulted in a significant reduction in airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, including IL-4, IL-5, and IL-13. An analysis of the BAL fluid suggested that Hsp70 is critically required for eosinophilic infiltration, collagen accumulation, and Th2 cytokine production in allergic airways. Furthermore, our bone marrow (BM) transfer studies show that SEA-induced airway inflammation, goblet cell hyperplasia, and Th2 cytokine production were attenuated in WT mice that were reconstituted with Hsp70-deficient BM, but these effects were not attenuated in Hsp70-deficient mice that were reconstituted with WT BM. Together, these studies identify a pathogenic role for Hsp70 in hematopoietic cells during allergic airway inflammation; this illustrates the potential utility of targeting Hsp70 to alleviate allergen-induced Th2 cytokines, goblet cell hyperplasia, and airway inflammation.

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

“…Lungs were homogenized using Qiagen tissue homogenizer and beads (Qiagen), and total RNA was extracted from lung tissues using RNeasy mini kit (Qiagen Science, Valencia, CA) as previously described ( 10 , 25 ). Lung RNA samples were reverse transcribed into cDNA using Superscript III (Invitrogen), and the relative transcript expression of select genes was measured using SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA) and the CFX384 Touch Real-Time PCR detection system (Bio-Rad, Hercules, CA) as previously described ( 35 ). Gene transcripts were normalized to the housekeeping gene transcripts such as hypoxanthine-guanine phosphoribosyltransferase (HPRT) or β actin and were expressed as the relative fold-induction change compared to the gene expression level of the control wildtype mice treated with saline solution.…”

HSP70-Mediated NLRP3 Inflammasome Suppression Underlies Reversal of Acute Kidney Injury Following Extracellular Vesicle and Focused Ultrasound Combination Therapy

“…We next sought to validate the mechanistic link between HSPs and the NLRP3 inflammasome. HSP90 has already been documented to positively regulate the NLRP3 inflammasome [35][36][37], but HSP70 has a less straightforward role [38][39][40], leading us to further investigate the latter. We treated human embryonic kidney (HEK) cells with either an HSP70 siRNA or with 7BIO (a non-apoptotic cell death inducer).…”

Investigation of molecular mechanisms of experimental compounds in murine models of chronic allergic airways disease using synchrotron Fourier-transform infrared microspectroscopy

“…Our results suggested type I collagen, typically attributed to α-helical structures at 1,336 cm −155 , which was increased in the OVA groups, and decreased in the saline and LSF groups. However, this peak may also be attributed to other α-helical-like structures such as heat shock proteins which are also known to be increased in asthma 56 . Furthermore, the saline and LSF treated groups, showed an increase in type III collagen deposition, characterized by an increase in β-sheet formations and random coil structures 57 .…”