Semaphorin 3E attenuates intestinal inflammation through the regulation of the communication between splenic CD11C + and CD4 + CD25 - T cells.

BACKGROUND AND PURPOSE: Alteration of the communication between the innate and adaptive immune cells is a hallmark of ulcerative colitis (UC). Semaphorin-3E (SEMA3E), a secreted guidance protein, regulates various immune responses.

EXPERIMENTAL APPROACH: We investigated SEMA3E expression in colonic biopsies of active UC patients and its mechanisms in Sema3e-/- mice using a UC model of experimental colitis.

KEY-RESULTS: SEMA3E level was decreased in active UC patients and negatively correlated with pro-inflammatory mediators. Colonic expression of SEMA3E was reduced in colitic Sema3e+/+ mice and recombinant (rec-) Plexin D1 treatment exacerbates the disease severity. In-vivo recombinant (rec)-SEMA3E treatment restored SEMA3E level in colitic Sema3e+/+ mice. In Sema3e-/- mice, the disease severity was increased and rec-SEMA3E abrogated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e-/- splenocytes and splenic CD11c+ cells produced more interleukin (IL)-12/23 and interferon (IFN)-γ compared to Sema3e+/+ , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, and NF-κB activator increased their production and abrogated the effect of rec-SEMA3E. Colitic Sema3e-/- splenic CD11c+ /CD4+ CD25- T cells co-culture resulted in higher production of IFN-γ and IL-17 when compared to colitic Sema3e+/+ splenic cells co-cultures, and rec-SEMA3E decreased these effects. In-vitro, anti-IL-12p19 and -12p35 antibodies and rec-IL-12 and -23 treatment confirmed the cross-talk between CD11c+ /CD4+ CD25- T cells.

CONCLUSION AND IMPLICATIONS: SEMA3E is reduced in colitis and modulates the colonic inflammation by regulating the interaction between CD11c+ and CD4+ CD25- T cells via an NF-κB dependent mechanism. Thus, SEMA3E can be a potential therapeutic target for UC patients.