TL1A Aggravates Cytokine-Induced Acute Gut Inflammation and Potentiates Infiltration of Intraepithelial Natural Killer Cells in Mice
Research output: Contribution to journal › Journal article › Research › peer-review
Peter Tougaard, Louise Otterstrøm Martinsen, Line Fisker Zachariassen, Lukasz Krych, Dennis Sandris Nielsen, Terkild Brink Buus, Anders Elm Pedersen, Axel Kornerup Hansen, Søren Skov, Camilla Hartmann Friis Hansen
The tumor necrosis factor alpha (TNFα)–homologous cytokine TL1A is emerging as a major player in intestinal inflammation. From in vitro experiments on human lymphocytes, TNF-like molecule 1A (TL1A) is known to activate a highly inflammatory lymphoid response in synergy with interleukin (IL)-12 and IL-18. Carriers of specific genetic polymorphisms associated with IL-12, IL-18, or TL1A signaling have increased Crohn’s disease risk, and all 3 cytokines are upregulated during active disease. The study aim was to investigate whether the type 1–polarizing cytokines IL-12 and IL-18 could directly initiate intestinal pathology in mice and how TL1A would influence the resulting inflammatory response.
Conventional barrier-bred and germ-free mice were randomly allocated to different groups and injected twice with different combinations of IL-12, IL-18, and TL1A, and killed 3 days after the first injection. All treatment groups were co-housed and fed a piroxicam-supplemented chow diet.
Intestinal pathology was evident in IL-12- and IL-18-treated mice and highly exacerbated by TL1A in both the colon and ileum. The cytokine-induced intestinal inflammation was characterized by epithelial damage, increased colonic levels of TNFα, IL-1β, IFN-γ, and IL-6, and various chemokines along with gut microbiota alterations exhibiting high abundance of Enterobacteriaceae. Furthermore, the inflamed ileum and colon exhibited a TL1A-specific increased infiltration of intraepithelial natural killer cells co-expressing NKG2D and IL-18Ra and a higher frequency of unconventional T cells in the colonic epithelium. Upon cytokine injection, germ-free mice exhibited similar intraepithelial lymphoid infiltration and increased colonic levels of IFNγ and TNFα.
This study demonstrates that TL1A aggravates IL-12- and IL-18-induced intestinal inflammation in the presence and absence of microbiota.
|Journal||Inflammatory Bowel Diseases|
|Publication status||Published - 2019|
- intraepithelial lymphocytes, NKG2D, cytokine synergy