bims-inflin 2023-10-01 papers

Issue of 2023‒10‒01
four papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

bioRxiv. 2023 Sep 15. pii: 2023.09.14.557714. [Epub ahead of print]

Sequentially activated death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling.

Ronit Schwartz Wertman, Christina K Go, Benedikt S Saller, Olaf Groß, Phillip Scott, Igor E Brodsky.

The Yersinia virulence factor YopJ potently inhibits immune signaling in macrophages by blocking activation of the signaling kinases TAK1 and IKK. In response, macrophages trigger a backup pathway of host defense that mediates cell death via the apoptotic enzyme caspase-8 and pyroptotic enzyme caspase-1. While caspase-1 is normally activated within multiprotein inflammasome complexes that contain the adaptor ASC and NLRs, which act as sensors of pathogen virulence, caspase-1 activation following Yersinia blockade of TAK1/IKK surprisingly requires caspase-8 and is independent of all known inflammasome components. Here, we report that caspase-1 activation by caspase-8 requires both caspase-8 catalytic and auto-processing activity. Intriguingly, while caspase-8 serves as an essential initiator of caspase-1 activation, caspase-1 amplifies its own activation through a feed-forward loop involving auto-processing, caspase-1-dependent cleavage of the pore-forming protein GSDMD, and subsequent activation of the canonical NLRP3 inflammasome. Notably, while caspase-1 activation and cell death are independent of inflammasomes during Yersinia infection, IL-1β release requires the canonical NLPR3 inflammasome. Critically, activation of caspase-8 and activation of the canonical inflammasome are kinetically and spatially separable events, as rapid capase-8 activation occurs within multiple foci throughout the cell, followed by delayed subsequent assembly of a single canonical inflammasome. Importantly, caspase-8 auto-processing normally serves to prevent RIPK3/MLKL-mediated necroptosis, and in caspase-8's absence, MLKL triggers NLPR3 inflammasome activation and IL-1β release. Altogether, our findings reveal that functionally interconnected but temporally and spatially distinct death complexes differentially mediate pyroptosis and IL-1β release to ensure robust host defense against pathogen blockade of TAK1 and IKK.One Sentence Summary: Yersinia -induced cell death and IL-1β release are driven by spatially and temporally distinct but functionally connected death complexes.

DOI: https://doi.org/10.1101/2023.09.14.557714

Am J Pathol. 2023 Sep 21. pii: S0002-9440(23)00362-0. [Epub ahead of print]

Toxoplasma gondii induces pyroptosis in human placental trophoblast and amniotic cells by inducing ROS production and activation of cathepsin B and NLRP1/NLRP3/NLRC4/AIM2 inflammasome.

Juan-Hua Quan, Fei Fei Gao, Tian-Zhong Ma, Wei Ye, Xiang Gao, Ming-Zhu Deng, Lan-Lan Yin, In-Wook Choi, Jae-Min Yuk, Guang-Ho Cha, Young-Ha Lee, Jia-Qi Chu.

Toxoplasma gondii infection in pregnant women may cause fetal anomaly; however, the underlying mechanisms remain unclear. Here, we investigated whether T. gondii induces pyroptosis in human placental cells and the underlying mechanisms. Human placental trophoblast (BeWo and HTR-8/SVneo) and amniotic (WISH) cells were infected with T. gondii, and then ROS production, cathepsin B (CatB) release, inflammasome activation, and pyroptosis induction were evaluated. Moreover, the molecular mechanisms of these effects were investigated by treating the cells with ROS scavengers, a CatB inhibitor, or inflammasome-specific siRNA. We found that T. gondii infection induced ROS generation and CatB release into the cytosol in placental cells but decreased mitochondrial membrane potential. T. gondii-infected human placental cells and villi showed NLRP1, NLRP3, NLRC4, and AIM2 inflammasome activation and subsequent pyroptosis induction, as evidenced by increased expression of ASC, cleaved caspase-1, and mature IL-1β and gasdermin D cleavage. In addition to inflammasome activation and pyroptosis induction, adverse pregnancy outcome was revealed in a T. gondii-infected pregnant mouse model. Administration of ROS scavengers, CatB inhibitor, or inflammasome-specific siRNA into T. gondii-infected cells reversed these effects. Collectively, these findings show that T. gondii induces NLRP1/NLRP3/NLRC4/AIM2 inflammasome-dependent caspase-1-mediated pyroptosis via induction of ROS production and CatB activation in placental cells, and this mechanism may play an important role in inducing cell injury in congenital toxoplasmosis.

Keywords: Congenital toxoplasmosis; Human placental cells; Inflammasomes; Pregnant mouse model; Pyroptosis; Toxoplasma gondii

DOI: https://doi.org/10.1016/j.ajpath.2023.08.016

Immun Inflamm Dis. 2023 Sep;11(9): e997

Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review.

Li Wei, Xufang Wang, Huifei Zhou.

BACKGROUND: Influenza virus (IV) is a leading cause of respiratory tract infections, eliciting responses from key innate immune cells such as Macrophages (MQs), Neutrophils, and Dendritic Cells (DCs). These cells employ diverse mechanisms to combat IV, with Inflammasomes playing a pivotal role in viral infection control. Cellular death mechanisms, including Pyroptosis, Apoptosis, and Necroptosis (collectively called PANoptosis), significantly contribute to the innate immune response.METHODS: In this updated review, we delve into the intricate relationship between PANoptosis and Inflammasomes within innate immune cells (MQs, Neutrophils, and DCs) during IV infections. We explore the strategies employed by IV to evade these immune defenses and the consequences of unchecked PANoptosis and inflammasome activation, including the potential development of severe complications such as cytokine storms and tissue damage.
RESULTS: Our analysis underscores the interplay between PANoptosis and Inflammasomes as a critical aspect of the innate immune response against IV. We provide insights into IV's various mechanisms to subvert these immune pathways and highlight the importance of understanding these interactions to develop effective antiviral medications.
CONCLUSION: A comprehensive understanding of the dynamic interactions between PANoptosis, Inflammasomes, and IV is essential for advancing our knowledge of innate immune responses to viral infections. This knowledge will be invaluable in developing targeted antiviral therapies to combat IV and mitigate potential complications, including cytokine storms and tissue damage.

Keywords: PANoptosis; inflammasome; influenza; innate immunity

DOI: https://doi.org/10.1002/iid3.997

Virulence. 2023 Dec;14(1): 2258057

The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation.

Yu-Xin Lei, Yang Liu, Li-Hua Xing, Yu-Jing Wu, Xue-Yin Wang, Fan-Hua Meng, Ya-Nan Lou, Zhao-Guo Ma, Lin Yuan, Shui-Xing Yu.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

Keywords: NLRP3 inflammasome; S. pluranimalium; extracellular trap; innate immunity; mixed lineage kinase-like protein

DOI: https://doi.org/10.1080/21505594.2023.2258057