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

ABSTRACT:

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.

SUBMITTER: Kermarrec L 

PROVIDER: S-EPMC6468259 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature