Astrocytes promote a protective immune response to brain<i>Toxoplasma gondii</i>infection via IL-33-ST2 signaling

Still, Katherine; Batista, Samantha J.; OʼBrien, Carleigh A.; Oyesola, Oyebola O.; Frueh, Simon; Webb, Lauren M.; Smirnov, Igor; Kovacs, Michael A.; Cowan, Maureen N.; Hayes, Nikolas W.; Thompson, Jeremy; Wojno, Elia D. Tait; Harris, Tajie H.

doi:10.1101/338400

Cited by 6 publications

(9 citation statements)

References 90 publications

(95 reference statements)

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“…Microglia have also been demonstrated to possess some potentially anti-parasitic functions [27][28][29][30][31] , but we are interested in investigating whether microglia perform specific, nonoverlapping functions distinct from infiltrating macrophages. Previous work from our lab has observed that while bloodderived monocytes and macrophages express high levels of the nitric oxide-generating enzyme iNOS in the brain during T. gondii infection, microglia lack this anti-parasitic molecule 43 . We hypothesize that even though they are in the same tissue microenvironment, microglia are unable to respond to the infection in the same way as infiltrating macrophages.…”

Section: Resultsmentioning

confidence: 80%

“…It has also been suggested that IL-1 can act on neurons, though it should be noted that it has also been reported that neurons express a unique form of IL-1RAcP which affects downstream signaling 69 . It is unclear whether astrocytes express IL-1R1, but astrocytes represent another radio-resistant cell population in the brain that has the ability to affect immune cell infiltration through chemokine production 14,43 . e Cyst burden per brain was determined by counting cysts in brain homogenate on a light microscope.…”

Section: Discussionmentioning

confidence: 99%

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Gasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

et al. 2020

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Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1β in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1β, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Gasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

et al. 2020

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“…Previous work from our lab has observed that while blood-derived monocytes and macrophages express high levels of the nitric oxide-generating enzyme iNOS in the brain during T. gondii infection, microglia markedly lack this anti-parasitic molecule. 29 This observation led to the hypothesis that even though they are in the same tissue microenvironment, microglia are unable to respond to the infection in the same way as infiltrating macrophages. Thus, we used a CX3CR1 Cre-ERT2 x ZsGreen fl/stop/fl mouse line that has been previously described as a microglia reporter line.…”

Section: Resultsmentioning

confidence: 99%

“…61 It is unclear whether astrocytes express IL-1R1, but astrocytes represent another radio-resistant cell population in the brain that has the ability to affect immune cell infiltration through chemokine production. 29, 62…”

Section: Discussionmentioning

confidence: 99%

Gasdermin-D-dependent IL-1αrelease from microglia promotes protective immunity during chronicToxoplasma gondiiinfection

Batista

Still

Johanson

et al. 2020

Preprint

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26Microglia, the resident immune cells of the brain parenchyma, are thought to be first-line defenders 27 against CNS infections. We sought to identify specific roles of microglia in the control of the 28 eukaryotic parasite Toxoplasma gondii, an opportunistic infection that can cause severe 29 neurological disease. In order to identify the specific function of microglia in the brain during 30 infection, we sorted microglia and infiltrating myeloid cells from infected microglia reporter mice. 31Using RNA-sequencing, we find strong NF-kB and inflammatory cytokine signatures 32 overrepresented in blood-derived macrophages versus microglia. Interestingly, we also find that 33 IL-1a is enriched in microglia and IL-1b in macrophages, which was also evident at the protein 34 level. We find that mice lacking IL-1R1 or IL-1a, but not IL-1b, have impaired parasite control 35 and immune cell infiltration specifically within the brain. Further, by sorting purified populations 36 from infected brains, we show that microglia, not peripheral myeloid cells, release IL-1a ex vivo. 37Finally, using knockout mice as well as chemical inhibition, we show that ex vivo IL-1a release is 38 gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in 39 immune infiltration into the brain and parasite control. These results demonstrate that microglia 40 and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii 41 infection, microglia specifically can release the alarmin IL-1a, a cytokine that promotes 42 neuroinflammation and parasite control. 43 44 45 46In this work, we have focused on IL-1, its expression by microglia and macrophages, as 70 well as its role in the brain during chronic T. gondii infection. IL-1 molecules include two main 71 cytokines: IL-1a and IL-1b. IL-1a can function as a canonical alarmin, which is a pre-stored 72 molecule that does not require processing and can be released upon cell death or damage, making 73 it an ideal candidate for an early initiator of inflammation. 19,20 In contrast, IL-1b is produced first 74 as a pro-form that requires cleavage by caspase-1 in order for it to be biologically active, rendering 75 IL-1b dependent on the inflammasome as a platform for caspase-1 activation. [21][22][23] Both of these 76 cytokines signal through the same receptor (IL-1R), a heterodimer of IL-1R1 and IL-1RAcP, with 77 similar affinity. 24 They also lack signal sequences and thus require a loss of membrane integrity to 78 be released. Caspase-mediate cleavage of gasdermin molecules has been identified as a major 79 pathway leading to pore formation and IL-1 release. 80The role of IL-1b and inflammasome pathways in T. gondii infection has been studied in 81 vitro as well as in rodent models of acute infection. In sum, these studies suggest roles for IL-1b, 82 IL18, IL-1R, NLRP1 and/or NLPR3 inflammasome sensors, the inflammasome adaptor protein 83 ASC, and inflammatory caspases-1 and -11. 25-28 However, the role of IL-1 signaling in the brain ...

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“…32,[35][36][37] While reactive astrocytes can be beneficial as in the case of spinal cord injury by forming a barrier between healthy and necrotic tissue or in Toxoplasma gondii infection by producing chemokines to recruit helpful immune cells, reactive astrocytes can also be detrimental. 38,39 A common feature of reactive astrocytes is the downregulation of genes involved in maintaining CNS homeostasis such as K ir 4.1, aquaporin 4, and neurotransmitter transporters and degrading enzymes. 40 Loss of the homeostatic functions of astrocytes is the most prominent feature of reactive astrocytes in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

et al. 2022

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Objective SCN8A epileptic encephalopathy is caused predominantly by de novo gain‐of‐function mutations in the voltage‐gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti‐seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy. Methods Using immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild‐type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+). Results Astrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium‐sensitive Kir4.1 currents compared to age‐matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures. Significance Astrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1‐mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.

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Astrocytes promote a protective immune response to brainToxoplasma gondiiinfection via IL-33-ST2 signaling

Abstract: SUMMARY 21An intact immune response is critical for survival of hosts chronically infected with 22Toxoplasma gondii. We observe clusters of macrophages surrounding replicating parasite in brain

Cited by 6 publications

References 90 publications

Gasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

Gasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

Gasdermin-D-dependent IL-1αrelease from microglia promotes protective immunity during chronicToxoplasma gondiiinfection

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

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