Abstract
Schistosomes control inflammation in their hosts via highly effective mechanisms such as induction of Tregs, Bregs, and alternatively activated macrophages (AAMs). Notably, IPSE/alpha-1, the major secretory product from Schistosoma mansoni eggs, triggers basophils to release interleukin (IL)-4 and IL-13. Both cytokines are essential for AAM induction, suggesting an important role for IPSE/alpha-1 in inflammation control. Here, we show by in vitro co-culture experiments that IPSE/alpha-1-induced basophil IL-4/IL-13 inhibited pro-inflammatory cytokine release from human LPS-activated monocytes. This effect was cell/cell contact-independent but dependent on IL-4, since it was abrogated in the presence of anti-IL-4 antibodies. Importantly, the IPSE/alpha-1-induced IL-4/IL-13 release from basophils was amplified in the presence of LPS. Moreover, monocytes co-cultured in the presence of LPS with IPSE/alpha-1-stimulated basophils adopted an AAM-like phenotype as assessed by elevated expression of CD206 and CD209. The putative in vivo relevance of these findings was supported by immunohistological staining of S. mansoni-infected murine tissue revealing close physical contact between IPSE/alpha-1 and basophils in schistosome egg granulomas. Taken together, we found that IPSE/alpha-1 dampens inflammatory cytokine responses by triggering basophil IL-4/IL-13, in particular in the context of TLR activation, thereby turning inflammatory monocytes into anti-inflammatory AAMs. This might represent a mechanism used by schistosomes to control inflammation in the host.
Highlights
Helminths have strong modulatory effects on the immune system of their hosts [1]
Since IPSE/alpha-1 is a general immunoglobulinbinding factor [17], with the potential to bind to receptors with immunoglobulin-like domains on the surface of cells and could activate or inhibit their functions, we investigated the effect of IPSE/alpha-1 by itself on monocytes
We demonstrated that IL-4/IL-13 produced by IPSE/alpha1-stimulated basophils inhibited the release of the proinflammatory cytokines IL-1β, IL-6 and TNF-α from LPSactivated monocytes
Summary
Helminths have strong modulatory effects on the immune system of their hosts [1]. For example, epidemiological studies and animal experiments have shown that helminth infections can protect against asthma, allergies and autoimmune diseases [2]. About 50% of the eggs are carried away with the blood stream and embolize in the liver, where they induce granulomatous inflammation. The other 50% migrate from the blood vessels through the intestinal tissue toward the gut lumen. In the process they induce mucosal granulomatous inflammation, leaving behind phlegmonous migration channels [3, 4]. Given the high number of eggs (and consequent perforation channels), one would expect extensive intestinal inflammation (and subsequent symptoms) in infected individuals. Experiments with S. mansoni-infected mice revealed that IL-4 and intact IL-4 receptor signaling is essential for the protection of mice from intestinal inflammation, presumably via induction of alternatively activated macrophages (AAMs) [7,8,9]. As a major source of IL-4 in helminth infections, including schistosomiasis, basophils have been identified [10,11,12]
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