Abstract:Serum amyloid A (SAA) is an acute phase inflammatory protein that we previously described as a robust biomarker of colorectal inflammation in patients with ulcerative colitis (UC) in clinical remission. However, what induces SAA expression in UC remains unclear. This study demonstrates that SAA is significantly expressed in the intestinal tract of UC mouse models when compared with C-reactive protein, another inflammatory biomarker. Moreover, interleukin-6 and tumor necrosis factor-α were found to promote SAA1… Show more
“…In humans, SAA1 and SAA2 are considered acute phase reactants, whereas in pigs, the SAA3 isoform is the major acute phase protein induced in response to an inflammatory stimulus ( 56 ), which was also shown in the present study. TNFα is one of the major inducers of SAA synthesis in the liver, and it has also been shown that the production of SAA is increased in intestinal epithelial cells following TNFα stimulation, possibly contributing to the development of inflammatory bowel disease ( 57 , 58 ). In urothelial cells, expression of SAA has been shown to increase upon infection with uropathogenic bacteria E.coli ( 59 ), whereas Lannergard et al.…”
Urothelial cells of the urinary bladder play a critical role in the development and progression of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic and debilitating inflammatory disease. Given the lack of data on the exact phenotype and function of urothelial cells in an inflammatory setting (as in IC/BPS), we performed the first in-depth characterization of these cells using RNA sequencing, qPCR, ELISA, Western blot, and immunofluorescence. After TNFα stimulation, urothelial cells in the in vitro model of IC/BPS showed marked upregulation of several proinflammatory mediators, such as SAA, C3, IFNGR1, IL1α, IL1β, IL8, IL23A, IL32, CXCL1, CXCL5, CXCL10, CXCL11, TNFAIPR, TNFRSF1B, and BIRC3, involved in processes and pathways of innate immunity, including granulocyte migration and chemotaxis, inflammatory response, and complement activation, as well as TLR-, NOD-like receptor- and NFkB-signaling pathways, suggesting their active role in shaping the local immune response of the bladder. Our study demonstrates that the TNFα-stimulated urothelial cells recapitulate key observations found in the bladders of patients with IC/BPS, underpinning their utility as a suitable in vitro model for understanding IC/BPS mechanisms and confirming the role of TNFα signaling as an important component of the associated pathology. The present study also identifies novel upregulated gene targets of TNFα in urothelial cells, including genes encoding the acute phase protein SAA, complement component C3, and the cytokine receptor IFNGR1, which could be exploited as therapeutic targets of IC/BPS. Altogether, our study provides a reference database of the phenotype of urothelial cells in an inflammatory environment that will not only increase our knowledge of their role in IC/BPS, but also advance our understanding of how urothelial cells shape tissue immunity in the bladder.
“…In humans, SAA1 and SAA2 are considered acute phase reactants, whereas in pigs, the SAA3 isoform is the major acute phase protein induced in response to an inflammatory stimulus ( 56 ), which was also shown in the present study. TNFα is one of the major inducers of SAA synthesis in the liver, and it has also been shown that the production of SAA is increased in intestinal epithelial cells following TNFα stimulation, possibly contributing to the development of inflammatory bowel disease ( 57 , 58 ). In urothelial cells, expression of SAA has been shown to increase upon infection with uropathogenic bacteria E.coli ( 59 ), whereas Lannergard et al.…”
Urothelial cells of the urinary bladder play a critical role in the development and progression of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic and debilitating inflammatory disease. Given the lack of data on the exact phenotype and function of urothelial cells in an inflammatory setting (as in IC/BPS), we performed the first in-depth characterization of these cells using RNA sequencing, qPCR, ELISA, Western blot, and immunofluorescence. After TNFα stimulation, urothelial cells in the in vitro model of IC/BPS showed marked upregulation of several proinflammatory mediators, such as SAA, C3, IFNGR1, IL1α, IL1β, IL8, IL23A, IL32, CXCL1, CXCL5, CXCL10, CXCL11, TNFAIPR, TNFRSF1B, and BIRC3, involved in processes and pathways of innate immunity, including granulocyte migration and chemotaxis, inflammatory response, and complement activation, as well as TLR-, NOD-like receptor- and NFkB-signaling pathways, suggesting their active role in shaping the local immune response of the bladder. Our study demonstrates that the TNFα-stimulated urothelial cells recapitulate key observations found in the bladders of patients with IC/BPS, underpinning their utility as a suitable in vitro model for understanding IC/BPS mechanisms and confirming the role of TNFα signaling as an important component of the associated pathology. The present study also identifies novel upregulated gene targets of TNFα in urothelial cells, including genes encoding the acute phase protein SAA, complement component C3, and the cytokine receptor IFNGR1, which could be exploited as therapeutic targets of IC/BPS. Altogether, our study provides a reference database of the phenotype of urothelial cells in an inflammatory environment that will not only increase our knowledge of their role in IC/BPS, but also advance our understanding of how urothelial cells shape tissue immunity in the bladder.
“…The mechanism behind this is that SAA3 upregulates IL-22 expression in colon mucosal neutrophils through a TLR2-dependent signal pathway, which can restrain chronic inflammation [ 63 – 67 ]. Interestingly, rectal expression of SAA3 is significantly increased by IL-22 [ 68 ]. Fig.…”
Section: Saa In the Pathogenesis Of Ibdmentioning
confidence: 99%
“…It has been reported that SAA expression could be induced by bacterial-derived products. Specifically, bacterial lipopolysaccharides could promote SAA expression [ 43 , 68 ]. In addition, the segmented filamentous bacteria adhering to mice intestinal epithelial cells could cause an accumulation of TH17 cells in the lamina propria, whose SAA1-3 transcriptions are significantly upregulated [ 82 ].…”
Inflammatory bowel diseases (IBD) is featured by gastrointestinal inflammation and a disease course with alternating recurrence and remission. The global burden caused by IBD has significantly boosted in recent years, necessitating treatment optimization. Serum amyloid A (SAA) is a class of 104 amino acid conservative acute-phase proteins, which is essential in immune-mediated inflammatory processes, like IBD. The SAA monomeric structure is composed of four α-helical regions and a C-terminal amorphous tail. Its disordered structure enables multiple bindings to different ligands and permits multiple functions. It has been proven that SAA has dual roles in the inflammatory process. SAA stimulates the pro-inflammatory cytokine expression and promotes the pathogenic differentiation of TH17 cells. In addition, SAA can remove toxic lipids produced during inflammatory responses and membrane debris from dead cells, redirect HDL, and recycle cholesterol for tissue repair. In IBD, SAA acts on gut epithelium barriers, induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Owing to the tight connection between SAA and IBD, several clinical studies have taken SAA for a biomarker for diagnosis, assessing disease activity, and predicting prognosis in IBD. Furthermore, 5-MER peptide, a drug specifically targeting SAA, has shown anti-inflammatory effects in some SAA-dependent animal models, providing novel insights into the therapeutic targets of IBD.
“…5A). Serum amyloid A (SAA) is a major protein marker of colitis disease activity, 47,48 and promotes intestinal inflammation. 49 Furthermore, we measured the protein level of SAA in the serum to gain further insight into the suppression of colitis by ADNs.…”
Section: Adns Reduce the Expression Of Pro-inflammatory Cytokines And...mentioning
Allium tuberosum-derived nanovesicles (ADNs) show anti-inflammatory effects in colitis models, reducing inflammatory factors and restoring gut microbial composition.
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