Spontaneous onset of TNFα‐triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H‐2 haplotype

Abstract

Recently, we established a doxycycline-inducible human tumor necrosis factor alpha (TNFα)-transgenic mouse line, ihTNFtg. Non-induced young and elderly mice showed low but constitutive expression of hTNFα due to promoter leakiness. The persistently present hTNFα stimulated endogenous pro-inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFα. The continuous upregulation of pro-inflammatory mTNFα 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 hTNFα 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 hTNFα 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: TNFα 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.

Identification of immune-related hub genes contributing to the pathogenesis, diagnosis, and remission of ulcerative colitis by integrated bioinformatic analyses

“…Wu F et al [ 32 ] elucidated that S100A9 upregulated in trinitrobenzene sulfonic acid-induced murine colitis and could be regulated by NF-κB inhibition. Leite Dantas R et al [ 33 ] demonstrated that S100A8/A9 alarmins in one of the determinants of Spontaneous onset of colonic inflammation which triggered TNFα.…”