| First Author | Leite Dantas R | Year | 2020 |
| Journal | J Pathol | Volume | 251 |
| Issue | 4 | Pages | 388-399 |
| PubMed ID | 32449525 | Mgi Jnum | J:298955 |
| Mgi Id | MGI:6470133 | Doi | 10.1002/path.5473 |
| Citation | Leite Dantas R, et al. (2020) Spontaneous onset of TNFalpha-triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H-2 haplotype. J Pathol 251(4):388-399 |
| abstractText | Recently, we established a doxycycline-inducible human tumor necrosis factor alpha (TNFalpha)-transgenic mouse line, ihTNFtg. Non-induced young and elderly mice showed low but constitutive expression of hTNFalpha due to promoter leakiness. The persistently present hTNFalpha stimulated endogenous pro-inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFalpha. The continuous upregulation of pro-inflammatory mTNFalpha and mS100A8/A9 proteins, due to their mutual expression dependency, gradually led to increased levels in colon tissue and blood. This finally exceeded the threshold levels tolerated by the healthy organism, leading to the onset of intestinal inflammation. Here, recombinant hTNFalpha functioned as an initial trigger for the development of chronic inflammation. Crossing ihTNFtg mice with S100A9(KO) mice lacking active S100A8/A9 alarmins or with Rag1(KO) mice lacking T and B lymphocytes completely abrogated the development of colonic inflammation, despite the still leaky hTNFalpha promoter. Furthermore, both the intensity of the immune response and the strength of immunosuppressive Treg induction was found to depend on the major histocompatibility complex (MHC) genetic composition. In summary, the onset of intestinal inflammation in elderly mice depends on at least four factors that have to be present simultaneously: TNFalpha upregulation, S100A8/A9 protein expression, functional T lymphocytes and genetic composition, with the MHC haplotype being of central importance. Only joint action of these factors leads to chronic intestinal inflammation, while absence of any of these determinants abrogates the development of the autoimmune disorder. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
