IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis

Abstract

To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-γ, TNF-α, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity. In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.

Lack of antigen-specific Th1 response alters granuloma formation and composition inSchistosoma mansoni-infected MyD88-/- mice

“…In confirmation, schistosome-infected IFN-c receptor-deficient and IFNc-deficient mice displayed, and the administration of anti-IFN-c antibody to infected mice resulted in, increased fibrosis and diminished granuloma size and cellularity [26][27][28][29]. In addition, exogenous application of IFN-c has been shown to reduce collagen levels [30], and increased secretion of IFN-c has anti-fibrotic actions [31]. These observations strikingly correlate with our results and leave little doubt that the reduction in Th1 responses (signified by the absence of IFN-c) was responsible for the changes in liver pathology as displayed in Fig.…”

Manson's schistosomiasis in the undernourished mouse: some recent findings

“…This may reflect a counter-regulatory response to increased levels of pro-inflammatory cytokines. Although a previous study has shown that IL-10 plays a central regulatory role in the pathogenesis of schistosomiasis (Hoffman et al 2000), its relationship to the nutritional status has not been studied (Coutinho et al 2005).…”

IL-4 and IFN-γ induced by human immunodeficiency virus vaccine in a schistosome infection model

“…Hoffmann and colleagues clearly demonstrated that in schistosome-infected mice, IL-10 significantly suppressed type 1 and type 2 cytokines' development in IL-4 --and IL-12 --deficient mice, respectively, and thereby impeded the development of severe egg-induced pathology in the single cytokine-deficient animals. 33 To further define the contribution of IL-10 in persistent infections, Hesse generated the IL-10/recombination-activating gene (RAG)2 -deficient mice and demonstrated that innate effectors and regulatory T…”