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

Background and Purpose: An alteration in 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 the expression of SEMA3E in colonic biopsies of active UC patients and its mechanisms in Sema3e ^-/- mice using an experimental model of UC.
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 exacerbated disease severity. In vivo rec-SEMA3E treatment restored SEMA3E level in colitic Sema3e ^+/+ mice. In Sema3e ^-/- mice, disease severity was increased, and rec-SEMA3E ameliorated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e ^-/- splenocytes and splenic CD11c ⁺ cells produced more IL-12/23 and IFN-γ compared to Sema3e ^+/+ , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, whereas an NF-κB activator increased their production and attenuated the effect of rec-SEMA3E. Colitic Sema3e ^-/- splenic CD11c ⁺ /CD4 ⁺ CD25 ^- T-cell co-cultures produced higher concentrations of IFN-γ and IL-17 when compared to colitic Sema3e ^+/+ splenic cell 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 crosstalk between CD11c ⁺ and CD4 ⁺ CD25 ^- T-cells.
Conclusion and Implications: SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c ⁺ and CD4 ⁺ CD25 ^- T-cells via an NF-κB-dependent mechanism. Thus, SEMA3E could be a potential therapeutic target for UC patients.
(© 2019 The British Pharmacological Society.)