Toll-like receptor-4 differentially mediates intestinal and extra-intestinal immune responses upon multi-drug resistant Pseudomonas aeruginosa association of IL10^−/− mice with chronic colitis

We therefore perorally challenged conventionally colonized TLR4-deficient IL10^−/− mice and IL10^−/− counterparts displaying comparably severe chronic colitis with a clinical MDR PA strain. PA could more sufficiently establish in the intestinal tract of TLR4-deficient IL10^−/− mice until day 14 postinfection (p.i.), whereas within 48 h the majority of IL10^−/− mice had already expelled the opportunistic pathogen from their guts. Intestinal colonization properties of PA in TLR4-deficient IL10^−/− mice were associated with distinct genotype-dependent differences in gut microbiota compositions before challenge given that TLR4-deficient IL10^−/− mice harbored more fecal enterobacteria and enterococci, but lower Clostridium/Eubacterium burdens. At day 14 p.i., PA-induced increases in colonic immune cells such as macrophages, monocytes and T-lymphocytes could be observed in TLR4-deficient IL10^−/− mice, but not IL10^−/− counterparts, that were accompanied by a more distinct secretion of IFN-γ in the colon and TNF in the mesenteric lymph nodes (MLN) of the former as compared to the latter. Conversely, splenic TNF levels were lower in TLR4-deficient IL10^−/− mice as compared to IL10^−/− controls at day 14 p.i. Interestingly, more pronounced apoptotic responses could be assessed in colonic epithelia of PA-challenged IL10^−/− mice only. This was paralleled by enhanced pro-inflammatory cytokine secretion not only in the intestines, but also in extra-intestinal compartments of IL10^−/− mice as indicated by increased concentrations of nitric oxide in the colon, IFN-γ in the MLN and IL-12p70 in the spleen at day 14 p.i.

Under chronic intestinal inflammatory conditions including IL10^−/− colitis MDR PA-association results in well-orchestrated TLR4-dependent immune responses both in intestinal and extra-intestinal compartments. Further studies should unravel the underlying molecular mechanisms in more detail.