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Oligodendrocyte-derived IL-33 functions as a microglial survival factor during neuroinvasive flavivirus infection

ABSTRACT: In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE241804 | GEO | 2023/11/08

REPOSITORIES: GEO

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The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8 T cells in chronic viral infection (RNA-Seq II)

Project description:T-cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these memory-like CD8 T cell (CD8ML) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection we identify the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8ML as well as for virus control. IL-33 receptor- (ST2-) deficient CD8 T cells exhibit biased end-differentiation and premature loss of Tcf-1. Intriguingly, ST2-deficient CD8ML responses are restored by blockade of type I interferon signaling, suggesting that opposing IFN-I and IL-33 effects control CD8ML formation in chronic infection. IL-33 signals broadly augment chromatin accessibility in CD8ML and determine these cells’ re-expansion potential. Our study identifies the IL-33 – ST2 axis as an important CD8ML-promoting pathway in the context of chronic viral infection.

2023-04-06 | GSE210538 | GEO

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8 T cells in chronic viral infection (RNA-Seq I)

2023-04-06 | GSE210537 | GEO

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8 T cells in chronic viral infection (ATAC-Seq)

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Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

Project description:Cryptococcal disease pathogenesis is associated with the induction of type 2 immune response which is largely mediated by adaptive T helper cells. Recently, epithelial cell-derived IL-33 and IL-25 are recognized as key mediators in driving pathogenic type 2 inflammation during C. neoformans infection. Although IL-25 and IL-33 exhibit a combinatorial and closely related function, the differential effect of these cytokines in the regulation of host immune response against C. neoformans infection is still elusive. We observed a predominantly increase of IL-25/IL-33 responsive Th cells within the lung after infection, especially at the chronic infection phase. The ex vivo stimulation of cryptococcal-specific Th cells demonstrated combinatorial effect of IL-25 and IL-33 in promoting the production of type 2 cytokines. A comparative transcriptomic analysis revealed coordinatel effects of these cytokines in promoting activation, survival, and homeostasis of adaptive Th cells during C. neoformans infection. The expression of type 2 cytokines and chemokine was absent in Th cells of Il17rb-/- mice, indicating the requirement of IL-25-mediated Th2-type immune responses during C. neoformans infection. Further analysis of the degree of virulence indicated a positive correlation between the frequency of IL-17RB/ST2-expressing Th cells and cryptococcal brain dissemination in vivo.

2023-06-18 | GSE229703 | GEO

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [shotgun sequencing]

Project description:IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals, and that single nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production by innate lymphoid cells (ILCs), but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33´s influence on antibacterial defense was dependent on housing conditions of the mice, and mediated by the modulatory effect of IL-33 on the intestinal microbiota. Collectively, we reveal that IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota. Our study thus provides insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection.

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IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [scRNA-seq]

2024-03-19 | GSE236342 | GEO

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [bulk RNA-seq]

Project description:IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals, and that single nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production by innate lymphoid cells (ILCs), but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33´s influence on antibacterial defense was dependent on the housing conditions of the mice, and mediated by IL-33´s modulatory effect on the intestinal microbiota. Collectively, we reveal that IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota. Our study thus provides insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection.

2024-03-19 | GSE236341 | GEO

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Project description:We report a novel mechanism of the interaction between perivascular cell and TAMs in promoting metastasis through the IL-33-ST2-dependent pathway. IL-33 was the highest up-regulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Il33-/- deficient mice showed impaired TAM recruitment and metastasis. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibited TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocked PDGF-BB-induced TAM recruitment and metastasis. High IL-33 in human cancers correlated with poor survival prognosis. These findings shed novel mechanisms of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

2016-05-03 | GSE69402 | GEO

mRNA-seq of thymic epithelial cells from PBS or IL-33 treated thymus

Project description:Severe infection commonly results in T cell aging, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrated that severe infection-induced IL-33 production resulted in acute thymic involution-mediated naive T cell aging and impaired host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrated that IL-33 triggered excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbed mTEC/cortical TEC (cTEC) compartment and caused acute thymic involution during severe infection. More importantly, IL-33 deficiency or IL-33 receptor ST2 deficient thymus transplantation rescued T-cell immunity to better control infection in mice. Our findings not only uncover a novel link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.

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