IL‐33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii

Abstract

T1/ST2 is an immunoregulatory protein of the IL-1 receptor family that has recently been reported as being a component of the IL-33 receptor. IL-33 is a newly described cytokine known to amplify the Th2 response and reduce production of Th1 cytokines. The function of T1/ST2 during Toxoplasma gondii infection is as yet undescribed. Given the requirement of a balanced type 1/type 2 response for effective control of parasite number and immunopathology, it is likely that T1/ST2 may play a part in aiding this process. Accordingly, we have shown that T1/ST2 mRNA transcripts are upregulated in the brains of mice infected with T. gondii and that mice deficient in T1/ST2 demonstrated increased susceptibility to infection with T. gondii that correlated with increased pathology and greater parasite burden in the brains. Real-time PCR analysis of cerebral cytokine levels revealed increased mRNA levels of iNOS, IFN-c and TNF-a in infected T1/ST2 À/À mice. These effects were independent of changes in IL-10 production. This study provides the first evidence of a specific role for IL-33 receptor signalling in the brain as well as highlighting the requirement of this mechanism in limiting infection with an intracellular parasite.Key words: Encephalitis . IL-33 . IL-33 receptor . Th1/Th2 . Toxoplasma IntroductionThe receptor T1/ST2 is a member of the IL-1 receptor family that also includes the TLR and the IL-18R [1]. Further characterisation revealed that differential splicing of T1/ST2 mRNA led to production of two different transcripts encoding either a transmembrane form (ST2L) or a soluble, secreted form (sST2) [2]. T1/ST2 is expressed by a number of haematopoetic cells such as T cells, mast cells, macrophages, NK cells and invariant NKT cells [3][4][5][6][7]. ST2L has previously been used as a marker for Th2 cells although T1/ST2-negative Th2 cells exist with reports that ST2L may be better described as a marker of effector Th2 cells enhancing the Th2 response rather than aiding its development [3,[8][9][10]. As well as promoting a Th2 response ST2L has been shown to sequester the signalling molecules MyD88 and Mal to inhibit subsequent cytokine production following TLR ligation [10]. sST2 also plays a role in downregulating the inflammatory response [6,11]. 426T1/ST2 is the ligand-binding component of the receptor for the cytokine IL-33 which, together with the IL-1 receptor accessory protein, forms the IL-33 receptor [12,13]. IL-33 is a member of the IL-1 family with the ability to downregulate IFN-g production by Th1 cells in vitro and upregulate the production of the Th2 cytokines IL-5 and IL-13 from Th2 cells both in vitro and in vivo [12]. Therefore, the function of IL-33 reinforces the previously described role of T1/ST2 in enhancing a Th2 response while reducing a Th1 response.Protective immunity to the protozoan parasite Toxoplasma gondii relies on a delicate balance of type 1/type 2 immune responses to effectively control parasite proliferation and prevent pathology caused by an over-exuberant type-1 response [14]...

Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases

“…During toxoplasmosis, cytokines and chemokines are regulated with a delicate balance between a necessary Th1 response for the control of parasite proliferation and a Th2 regulating response to limit the pathology due to an exacerbated deleterious Th1 response (84). ST2 was overexpressed in the brains of mice infected with Toxoplasma gondii (85). In BALB/c mice, ST2 deficiency increased susceptibility to cerebral infection characterized by an increased parasite load and more severe encephalitis due to increased levels of iNOS, TNF-␣, and IFN-␥.…”

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…28 Similar to the effects of UV, IL-33 has potent immunemodulating properties that are mediated by the induction of cytokines including IL-1, -4, -6, -10. and -13, as well as chemokines such as CXCL8, CCL2, CCL3, and CCL5. 22,23,29,30 Consequently, although IL-33 can reduce the development of atheroscleoris 31 and prevent the development of parasitic-induced encephalitis, 32 it may also promote the development of asthma 33 and ar-thritis. 29 Recently, the immune-modulating functions of IL-33 have been extended to include attenuation of bacterial sepsis via neutrophil recruitment 28 and the activation of newly discovered "nuocytes" for the effective elimination of parasitic infections.…”

ProtectiveToxoplasma gondii-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

“…Since IL-10 is mainly produced by conventional Foxp3 Ϫ Th1 cells in toxoplasmosis (17), the reduced level of IL-10 mRNA production is most probably caused by the impaired development of T. gondii-specific Th1 cells in PKC-Ϫ/Ϫ mice. Of note, in mice of the same T. gondii-resistant BALB/c background, IL-33 receptor-mediated downregulation of Th1 response is important to prevent intracerebral immunopathology and to control parasite growth in the brain (19). Thus, in BALB/c mice both the PKC--dependent activation of protective Th1 and Th2 responses (see below) and the IL-33-dependent limitation of Th1 responses are required for effective parasite control and prevention of an exacerbated encephalitis.…”