Macrophage Death following Influenza Vaccination Initiates the Inflammatory Response that Promotes Dendritic Cell Function in the Draining Lymph Node

Chatziandreou, Nikolaos; Farsakoglu, Yagmur; Palomino‐Segura, Miguel; D’Antuono, Rocco; Pizzagalli, Diego Ulisse; Sallusto, Federica; Lukacs‐Kornek, Veronika; Uguccioni, Mariagrazia; Corti, Davide; Turley, Shannon J.; Lanzavecchia, Antonio; Carroll, Michael; González, Santiago F.

doi:10.1016/j.celrep.2017.02.026

Cited by 52 publications

(63 citation statements)

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“…IL-1 α release from lymph node macrophages in an inflammasome-independent death event has been shown to enhance antigen presentation and humoral responses to influenza vaccination. 45 IL-1 α has been shown to initiate lung inflammation in a model of sterile inflammation using silica. 46 Recently, some reports have suggested IL-1 α rather than IL-1 β drives sepsis pathology.…”

Section: Discussionmentioning

confidence: 99%

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

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Johanson

et al. 2020

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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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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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“…Furthermore, it has been shown that vaccinia virus induces inflammasome activation and death of SCS macrophages by pyroptosis. This results in release of extracellular ASC specks which drive lymph node inflammation ( 39 ), while other work using an attenuated influenza vaccine has shown a role for TLR7 signaling in the death of SCS macrophages and subsequent IL-1α release ( 40 ). The previously shown partial reduction of ISCOMATRIX adjuvant activity in ASC and caspase- 1/11 deficient mice, and the ISCOMATRIX driven in vitro death of macrophages in combination with our data suggests that SCS macrophages may be a key point where innate immune activation plays a role in mediating ISCOMATRIX adjuvant activity ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo

et al. 2018

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Dendritic cell activation of CD4 T cells in the lymph node draining a site of infection or vaccination is widely considered the central event in initiating adaptive immunity. The accepted dogma is that this occurs by stimulating local activation and antigen acquisition by dendritic cells, with subsequent lymph node migration, however the generalizability of this mechanism is unclear. Here we show that in some circumstances antigen can bypass the injection site inflammatory response, draining freely and rapidly to the lymph nodes where it interacts with subcapsular sinus (SCS) macrophages resulting in their death. Debris from these dying SCS macrophages is internalized by monocytes recruited from the circulation. This coordinated response leads to antigen presentation by monocytes and interactions with naïve CD4 T cells that can drive the initiation of T cell and B cell responses. These studies demonstrate an entirely novel pathway leading to initiation of adaptive immune responses in vivo.

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“…Multi-Photon Intravital Video Microscopy (MP-IVM), in combination with image-based systems biology 1 , represent a key methodology for studying the interplay of cells in organs and tissues of living animals 2 . Indeed, recent analyses of leukocyte migration in MP-IVM data, highlighted unprecedented cell-to-cell interaction patterns such as antigen capturing 3 and presentation 4 , host-pathogen interaction 5 , 6 , tumor immune surveillance 7 and cell activation 8 amongst others. The advantage of MP-IVM with respect to other optical methods relies on the usage of multiple infrared photons.…”

Section: Background and Summarymentioning

confidence: 99%

Leukocyte Tracking Database, a collection of immune cell tracks from intravital 2-photon microscopy videos

et al. 2018

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Recent advances in intravital video microscopy have allowed the visualization of leukocyte behavior in vivo, revealing unprecedented spatiotemporal dynamics of immune cell interaction. However, state-of-the-art software and methods for automatically measuring cell migration exhibit limitations in tracking the position of leukocytes over time. Challenges arise both from the complex migration patterns of these cells and from the experimental artifacts introduced during image acquisition. Additionally, the development of novel tracking tools is hampered by the lack of a sound ground truth for algorithm validation and benchmarking. Therefore, the objective of this work was to create a database, namely LTDB, with a significant number of manually tracked leukocytes. Broad experimental conditions, sites of imaging, types of immune cells and challenging case studies were included to foster the development of robust computer vision techniques for imaging-based immunological research. Lastly, LTDB represents a step towards the unravelling of biological mechanisms by video data mining in systems biology.

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Macrophage Death following Influenza Vaccination Initiates the Inflammatory Response that Promotes Dendritic Cell Function in the Draining Lymph Node

Cited by 52 publications

References 50 publications

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

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

A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo

Leukocyte Tracking Database, a collection of immune cell tracks from intravital 2-photon microscopy videos

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