Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation

• Published in: Mediators of inflammation Vol. 2022; pp. 6049500 - 13
• Main Authors: Rodrigues, Bruno Lima, Dotti, Isabella, Pascoal, Lívia Bitencourt, Morari, Joseane, Esteller, Miriam, Coope, Andressa, Ayrizono, Maria de Lourdes Setsuko, Salas, Azucena, Leal, Raquel Franco
• Format: Journal Article
• Language: English
• Published: United States Hindawi 09.02.2022; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Activating transcription factor 3; Analysis; Apoptosis; Autophagy; BAX protein; Chaperones; Colitis, Ulcerative - metabolism; Colonoscopy; Cytokines; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Endoribonucleases - genetics; Endoribonucleases - metabolism; Endoscopy; Epithelial cells; Ethics; Gene expression; Genetic transcription; GRP78 protein; Humans; Hybridization; Immunohistochemistry; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Intestinal Mucosa - metabolism; Intestine; Kinases; Laboratories; Lamina propria; Molecular modelling; Mucosa; Protein folding; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proteolysis; Quantitative analysis; Software; Transcription; Transcription factors; Ulcerative colitis; Unfolded Protein Response; Brazil; United States > US; Germany
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2022/6049500

Ulcerative colitis (UC) is characterized by a chronic overproduction of proinflammatory cytokines. During an acute phase, the endoplasmic reticulum (ER) is overloaded and the protein folding process is impaired, a condition named ER stress. This state induces a response (unfolded protein response (UPR)), initiated by the activation of IRE1/Xbp-1, PERK/eIF2α, and ATF6 pathways, which has previously been linked to intestinal inflammation in experimental models. ER stress and UPR activation trigger the activation of proinflammatory, autophagy, and apoptosis genes, in addition to promoting protein degradation. Therefore, the goal of this study was to evaluate the activation of ER stress and UPR in colonic mucosa of UC patients. Patient and Methods. Transcriptional analysis of ER stress- and UPR-related genes was performed by qPCR from intestinal mucosa of patients with UC. We also performed in situ hybridization (ISH) and immunohistochemistry (IHQ) of PERK/eIF2α and IRE1/Xbp-1 pathways and UPR-related chaperones. Results. We first evaluated inflammatory genes via qPCR, and we observed that all analyzed proinflammatory transcripts were upregulated in UC patients. ISH and IHQ images showed that ER stress is activated via PERK/eIF2α and IRE1/Xbp-1 pathways not only in intestinal epithelial cells but also in cells of the lamina propria of UC colonic mucosa. Transcriptional analysis confirmed that EIF2AK3 was upregulated in UC patients. UPR-related genes, such as ATF3, STC2, and DDIT3, along with the chaperones and cochaperones DNAJC3, CALR, HSP90B1, and HSPA5, were also upregulated in UC patients. In addition, we observed that proapoptotic and autophagy genes (Bax and ATG6L1, respectively) were also upregulated. Conclusion. Our results suggest that ER stress and UPR are indeed activated in UC patients and this may contribute to the chronic inflammatory process seen in UC. The increased apoptosis and autophagy markers further support the activation of these findings once they are activated to counterbalance tissue damage. These findings provide new insights into the molecular mechanisms that maintain UC activity and open new possibilities to attenuate intestinal inflammation.