Fig. 5
Schematic representation of the proposed mechanisms of action of TNBS and L. lactis FnBPA+ (pValac::dts::IL-4). a In TNBS-induced colitis, ethanol (etOH) disrupts the mucosal barrier and allows translocation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The haptenization agent interacts with amine groups of colon and/or microbiota protein, binding trinitrophenyl groups to these proteins indiscriminately. Haptenized proteins are engulfed, processed and presented by antigen presenting cells (APCs) to T cells in the lamina propria. In the absence of appropriate regulatory mechanisms, this leads to excessive secretion of interleukin 12 (IL-12) by classically activated macrophages (mϕ) and induce an exaggerated T helper 1 (Th1) response—production of high levels of interferon γ (IFN-γ)—that leads to the production of other proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) by mϕ, which are the immediate cause of the intestinal inflammation [28, 52]. b Administration of L. lactis MG1363 FnBPA+ (pValac::dts::IL-4) possibly leads to its entry into epithelial cells (1) and/or transepithelial dendrites extended by resident mϕ to capture antigens in the lumen (2). This bacterium is then lysed and pValac::dts::IL-4 is released in the cytoplasm and translocated to the nucleus where the expression of the IL-4-coding sequence occurs [53]. Interleukin 4 (IL-4) secreted by transfected cells may contribute to the differentiation of T helper 2 (Th2) cells and consequently, may cooperate with the restoration of the levels of this cytokine which has a markedly inhibitory effect on the expression and release of Th1 cytokines [13]. Combination of IL-4 and bacterial products could then lead to the development of an alternatively activated mϕ population that participates in tissue remodeling and repair and produces high levels of the immunosuppressive cytokine interleukin 10 (IL-10). Through IL-10 production, these M2/hybrid mϕ appear to facilitate secondary expansion and maintenance of IL-10-producing Foxp3+ T regulatory (Treg) cells and consequently, regulate TNBS-induced colitis [49, 51, 54, 55]