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.
Highlights
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
Our bone marrow (BM) transfer studies show that soluble egg antigens (SEAs)-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
We further investigated whether the loss of Hsp70 was associated with a decrease in bronchial alveolar lavage fluid (BALF) eosinophilia
Summary
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. IL-5 is a primary cytokine that initiates the recruitment, activation, and survival of eosinophils in airway inflammation, whereas IL-13 is critical for AHR through different mechanisms, including the contraction of airway smooth muscle cells, goblet cell hyperplasia, and mucus hypersecretion [6] In support of these findings, clinical trials targeting Th2 cytokines have shown promising outcomes to improve the quality of life and to control asthma exacerbations [7, 8]. Asthmatic patients have elevated levels of Hsp in induced sputum and serum compared with healthy subjects, and this increase correlates with disease severity [23] Those studies have suggested a proinflammatory role for Hsp in the development of allergic diseases, whereas other reports have described Hsp as an anti-inflammatory mediator [24]. Few studies have examined the relationship among Hsp, the Th2 immune responses, and allergic airway inflammation
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