Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi

We have demonstrated recently that the glycoinositolphospholipid (GIPL) molecule from the protozoan Trypanosoma cruzi is a TLR4 agonist with proinflammatory effects. Here, we show that GIPL‐induced neutrophil recruitment into the peritoneal cavity is mediated by at least two pathways: one, where IL‐1β acts downstream of TNF‐α, and a second, which is IL‐1β‐ and TNFRI‐independent. Moreover, NKT cells participate in this proinflammatory cascade, as in GIPL‐treated CD1d−/− mice, TNF‐α and MIP‐2 levels are reduced significantly. As a consequence of this inflammatory response, spleen and lymph nodes of GIPL‐treated mice have an increase in the percentage of T and B cells expressing the CD69 activation marker. Cell‐transfer experiments demonstrate that T and B cell activation by GIPL is an indirect effect, which relies on the expression of TLR4 by other cell types. Moreover, although signaling through TNFRI contributes to the activation of B and γδ+ T cells, it is not required for increasing CD69 expression on αβ+ T lymphocytes. It is interesting that T cells are also functionally affected by GIPL treatment, as spleen cells from GIPL‐injected mice show enhanced production of IL‐4 following in vitro stimulation by anti‐CD3. Together, these results contribute to the understanding of the inflammatory properties of the GIPL molecule, pointing to its potential role as a parasite‐derived modulator of the immune response during T. cruzi infection.