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Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by the ingestion of gluten in genetically predisposed individuals. While the adaptive immune response to deamidated gliadin peptides represents a central pathogenic mechanism, growing evidence suggests that epithelial stress and innate immune activation play a fundamental role in the onset and persistence of the disease. Heat shock proteins (Hsps), central regulators of cellular proteostasis, have emerged as potential mediators at the interface between epithelial distress and immune signaling. This review discusses the involvement of major Hsp families, including Hsp27, Hsp60, Hsp70, and Hsp90, in the pathophysiology of CD. The altered expression of Hsp27 and Hsp70 in the intestinal mucosa reflects a persistent state of epithelial stress that often persists despite a strict gluten-free diet (GFD). We focus specifically on Hsp60, whose extracellular release under stress conditions may allow it to function as a damage-associated molecular pattern (DAMP), engaging Toll-like receptors and promoting NF-κB- and inflammasome-dependent inflammatory pathways. Although direct mechanistic evidence linking Hsp60 to CD remains limited, the convergence of epithelial stress signs, Toll-like receptor (TLR) upregulation, and prolonged innate immune activation supports the hypothesis of a stress-induced inflammatory amplification circuit in the coeliac mucosa. Further studies are essential to clarify the pathogenic relevance and potential therapeutic implications of this proposed axis.
Vergilio et al. (Tue,) studied this question.