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

Br J Pharmacol. 2019 May;176(9):1235-1250. doi: 10.1111/bph.14614. Epub 2019 Apr 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11c Antigen / metabolism*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / metabolism
  • Dextran Sulfate
  • Humans
  • Inflammation / metabolism*
  • Intestinal Mucosa / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Semaphorins / metabolism*
  • Spleen / metabolism

Substances

  • CD11c Antigen
  • SEMA3E protein, human
  • Semaphorins
  • Dextran Sulfate