bims-inflin 2024-12-01 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2024–12–01
nine papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

BCL2 regulates antibacterial autophagy in the intestinal epithelium.
Telomerase RNA component knockout exacerbates Staphylococcus aureus pneumonia by extensive inflammation and dysfunction of T cells.
The microneme protein1 (MIC1) of Chinese 1 Toxoplasma regulates pyroptosis through the TLR4/NLRP3 pathway in macrophages.
Chlamydia psittaci infection induces IFN-I and IL-1β through the cGAS-STING-IRF3/NLRP3 pathway via mitochondrial oxidative stress in human macrophages.
Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.
The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
Identification of a covalent NEK7 inhibitor to alleviate NLRP3 inflammasome-driven metainflammation.
Cadmium exposure triggers alveolar epithelial cell pyroptosis by inducing mitochondrial oxidative stress and activating the cGAS-STING pathway.
COVID-19 progression and convalescence in common variable immunodeficiency patients show dysregulated adaptive immune responses and persistent type I interferon and inflammasome activation.

Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410205121

BCL2 regulates antibacterial autophagy in the intestinal epithelium.

Yun Li, Shai Bel, Jamaal L Benjamin, Kelly A Ruhn, Brian Hassell, Cassie L Behrendt, Zheng Kuang, Lora V Hooper.

  Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium (Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium.

Keywords:  autophagy; enterocyte; innate immunity; intestinal epithelium; pathogenic bacteria

DOI:  https://doi.org/10.1073/pnas.2410205121
Elife. 2024 Nov 28. pii: RP100433. [Epub ahead of print]13

Telomerase RNA component knockout exacerbates Staphylococcus aureus pneumonia by extensive inflammation and dysfunction of T cells.

Yasmina Reisser, Franziska Hornung, Antje Häder, Thurid Lauf, Sandor Nietzsche, Bettina Löffler, Stefanie Deinhardt-Emmer.

  The telomerase RNA component (Terc) constitutes a non-coding RNA critical for telomerase function, commonly associated with aging and pivotal in immunomodulation during inflammation. Our study unveils heightened susceptibility to pneumonia caused by Staphylococcus aureus (S. aureus) in Terc knockout (Tercko/ko) mice compared to both young and old infected counterparts. The exacerbated infection in Tercko/ko mice correlates with heightened inflammation, manifested by elevated interleukin-1β (IL-1β) levels and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome within the lung. Employing mRNA sequencing methods alongside in vitro analysis of alveolar macrophages (AMs) and T cells, our study elucidates a compelling correlation between Tercko/ko, inflammation, and impaired T cell functionality. Terc deletion results in compromised T cell function, characterized by dysregulation of the T cell receptor and absence of CD247, potentially compromising the host's capacity to mount an effective immune response against S. aureus. This investigation provides insights into the intricate mechanisms governing increased vulnerability to severe pneumonia in the context of Terc deficiency, which might also contribute to aging-related pathologies, while also highlighting the influence of Terc on T cell function.

Keywords:  Staphylococcus aureus; T cells; Terc; aging; infectious disease; inflammation; microbiology; mouse; pneumonia

DOI:  https://doi.org/10.7554/eLife.100433
Parasit Vectors. 2024 Nov 29. 17(1): 495

The microneme protein1 (MIC1) of Chinese 1 Toxoplasma regulates pyroptosis through the TLR4/NLRP3 pathway in macrophages.

Wenze Sun, Fan Zhang, Jinjin Zhu, Yanxia Yu, Yang Wang, Qingli Luo, Li Yu.

   BACKGROUND: TgMIC1, a soluble adhesion protein that typically facilitates parasite invasion, exhibited varying expression levels among distinct virulence strains of Chinese 1 Toxoplasma. This study aims to explore its role in immunological regulation and its association with diverse postinfection outcomes in Toxoplasma infection.
METHODS: First, the mic1 knockout strain Wh3Δmic1 was generated and assessed for its virulence and proliferative capacity. Subsequently, the serum inflammation levels were examined in mice infected with Wh3Δmic1, Wh3, and Wh6. Furthermore, rMIC1 and rMIC1-T126A/T220A, which lack binding sites to N-glycan in TLR4, were produced for coculture with bone marrow-derived macrophages (BMDMs) to investigate their impact on pyroptosis.
RESULTS: Our data showed Wh3Δmic1 exhibited a significant reduction in invasion efficiency, limited growth, and attenuated inflammatory responses in mice. Additionally, it displayed a decreased capacity to induce pyroptosis when compared with Wh3-infected BMDMs. Moreover, rMIC1 but not rMIC1-T126A/T220A was found to be able to upregulate NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and activate GSDMD and caspase-1 in BMDMs but not in TLR4-/- and NLRP3-/- BMDMs.
CONCLUSIONS: TgMIC1 is implicated in both parasite invasion and the modulation of macrophage pyroptosis via the TLR4/NLRP3 pathway. This investigation indicates that TgMIC1 serves diverse functions in Toxoplasma gondii infection, thereby enhancing comprehension of the immune regulatory mechanisms of the parasite.

Keywords:   Toxoplasma gondii ; NLRP3; Pyrptosis; TLR4; TgMIC1

DOI:  https://doi.org/10.1186/s13071-024-06584-z
Vet Microbiol. 2024 Nov 16. pii: S0378-1135(24)00314-6. [Epub ahead of print]299 110292

Chlamydia psittaci infection induces IFN-I and IL-1β through the cGAS-STING-IRF3/NLRP3 pathway via mitochondrial oxidative stress in human macrophages.

Hongyu Yang, Peiyuan Sun, Shi Zhou, Yuanyuan Tang, Sijia Li, Weiwei Li, Xiang Yu, Hanying Liu, Yimou Wu.

  Chlamydia psittaci (C. psittaci) is a multi-host pathogen that elicits robust innate immune responses in macrophages. Chlamydiae target host mitochondria to manipulate the cellular fate and metabolic functions. However, the effect of C. psittaci on the host mitochondria remains obscure. This study investigated how C. psittaci, post-infection in human macrophages, induces mitochondrial oxidative stress and damage to activate the cGAS-STING-IRF3/NLRP3 pathway for IFN-I and IL-1β production. Results demonstrate that C. psittaci increased mitochondrial ROS (mtROS) production. This induced the release of oxidized mitochondrial DNA (mtDNA) into the cytoplasm of macrophages. It also augmented IFN-I and IL-1β production dependent on the cGAS-STING pathway. Macrophages pre-treated with mtROS inhibitor mito-TEMPO displayed reduced oxidized mtDNA. This consequently lowered IFN-I and IL-1β production via the cGAS-STING pathway induced by C. psittaci. Additionally, we found that mtROS production may inhibit C. psittaci proliferation through the synergistic action of IFN-I and IL-1β. In conclusion, our study reveals that C. psittaci induces mtROS production leading to mtDNA release. This activates the cGAS-STING-IRF3/NLRP3 pathway to increase IFN-I and IL-1β production. This study elucidates a novel mechanism of bacterial pathogen activation in the cGAS-STING pathway. This reveals the molecular mechanisms underlying the immune response to C. psittaci infection and proposes potential targets for the treatment of C. psittaci related diseases.

Keywords:  CGAS-STING; Chlamydia psittaci; Type I interferon; mtDNA; mtROS

DOI:  https://doi.org/10.1016/j.vetmic.2024.110292
Nat Commun. 2024 Nov 25. 15(1): 10142

Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.

Mustafa Titiz, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Matilde Marini, Viola Seravalli, Martina Chieca, Pasquale Pensieri, Marco Montini, Gaetano De Siena, Benedetta Pasquini, Silvia Vannuccini, Luigi Francesco Iannone, Thiago M Cunha, Giulia Brancolini, Elisa Bellantoni, Irene Scuffi, Alessandra Mastricci, Martina Tesi, Mariarosaria Di Tommaso, Felice Petraglia, Pierangelo Geppetti, Romina Nassini, Francesco De Logu.

Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis.

DOI: https://doi.org/10.1038/s41467-024-54486-6
Nat Commun. 2024 Nov 23. 15(1): 10163

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1038/s41467-024-54344-5
Cell Commun Signal. 2024 Nov 25. 22(1): 565

Identification of a covalent NEK7 inhibitor to alleviate NLRP3 inflammasome-driven metainflammation.

Xiangyu Jin, Yanqing Yang, Didi Liu, Xinru Zhou, Yi Huang.

  Aberrant activation of NLRP3 inflammasome is associated with a variety of inflammatory diseases. Advances in understanding the molecular mechanisms of NLRP3 inflammasome have revealed that NEK7 is an essential component for its activation, but the development of drugs specifically targeting NEK7 remains challenging. Here we identify rociletinib (ROC), an anticancer drug in phase III clinical trial with high safety profile, as a highly potent and specific small-molecule antagonists of NEK7. Mechanistically, ROC covalent binds to the cysteine 79 of NEK7 through its reactive α, β-unsaturated carbonyl group, thereby inhibiting the interaction between NLRP3 and NEK7, and the subsequent assembly and activation of NLRP3 inflammasome. Furthermore, ROC alleviates the pathological features of metainflammation on the mouse model of type 2 diabetes (T2D). In summary, our results identify ROC as a covalent inhibitor of NEK7 and demonstrates that targeting NEK7 provides a potential and promising strategy for the treatment of NLRP3 inflammasome-driven T2D.

Keywords:  Covalent binding; NEK7; NLRP3 inflammasome; Rociletinib; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12964-024-01919-w
Cell Commun Signal. 2024 Nov 26. 22(1): 566

Cadmium exposure triggers alveolar epithelial cell pyroptosis by inducing mitochondrial oxidative stress and activating the cGAS-STING pathway.

Chen-Yu Zhang, An-Jun Ou, Ling Jin, Nan-Shi-Yu Yang, Ping Deng, Cha-Xiang Guan, Xiao-Ting Huang, Jia-Xi Duan, Yong Zhou.

   BACKGROUND: Cadmium is a ubiquitous toxic metal and environmental pollutant. More and more studies have shown that cadmium exposure can damage lung function. Alveolar epithelial cells (AECs) are structural cells that maintain the stability of lung function. The injury of AECs is an essential determinant of many lung diseases. In the lung, cadmium accumulation can cause damage to AECs. However, the specific mechanism is still unclear. This study aimed to explore the key mechanism underlying the injury of AECs caused by cadmium exposure.
METHODS: The main modes of death of AECs induced by cadmium exposure were evaluated in vivo and in vitro. Transcriptomic changes of AECs induced by cadmium exposure were analyzed using RNA-sequence. Mitochondrial ROS scavengers (mitoQ), voltage-dependent anion channel 1 (VDAC1) oligomer inhibitor (VBIT4), and cyclic GMP-AMP synthase (cGAS) inhibitor (RU.521) were used to assess whether cadmium exposure triggered pyroptosis of AECs by inducing mitochondrial stress to activate the cGAS-STING-NLRP3 axis.
RESULTS: In this study, the expression of pyroptosis-related proteins was significantly up-regulated in the cadmium-exposed AECs, while the expression of apoptosis, necroptosis, and ferroptosis-related proteins had no significant up-regulated. The pan-caspase inhibitor ZVAD-FMK significantly reduced cell death. Thus, our research indicates that pyroptosis is the primary type of AEC death exported to cadmium. Mechanistically, RNA-seq and Western Blot results showed that cadmium exposure activated the cGAS-STING pathway in AECs and promoted pyroptosis by activating the NLRP3 inflammasome. Further investigation of the mechanism found that cadmium exposure caused mitochondrial oxidative stress, which led to mtDNA leakage into the cytoplasm and activated the cGAS-STING pathway. In addition, inhibition of the cGAS-STING pathway significantly alleviated lung injury induced by cadmium exposure in mice.
CONCLUSION: Our study confirmed that pyroptosis of AECs was a vital mechanism of lung injury after cadmium exposure in a cGAS-STING-dependent manner, which may provide a new target for the treatment of lung diseases induced by cadmium exposure.

Keywords:  Alveolar epithelial cells; Cadmium; NOD-like receptor protein 3 inflammasome; Pyroptosis; cGAS-STING

DOI:  https://doi.org/10.1186/s12964-024-01946-7
Nat Commun. 2024 Nov 28. 15(1): 10344

COVID-19 progression and convalescence in common variable immunodeficiency patients show dysregulated adaptive immune responses and persistent type I interferon and inflammasome activation.

Javier Rodríguez-Ubreva, Josep Calafell-Segura, Celia L Calvillo, Baerbel Keller, Laura Ciudad, Louis-François Handfield, Carlos de la Calle-Fabregat, Gerard Godoy-Tena, Eduardo Andrés-León, Regina Hoo, Tarryn Porter, Elena Prigmore, Maike Hofmann, Annegrit Decker, Javier Martín, Roser Vento-Tormo, Klaus Warnatz, Esteban Ballestar.

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency, marked by hypogammaglobulinemia, poor antibody responses, and increased infection susceptibility. The COVID-19 pandemic provided a unique opportunity to study the effects of prolonged viral infections on the immune responses of CVID patients. Here we use single-cell RNA-seq and spectral flow cytometry of peripheral blood samples before, during, and after SARS-CoV-2 infection showing that COVID-19 CVID patients display a persistent type I interferon signature at convalescence across immune compartments. Alterations in adaptive immunity include sustained activation of naïve B cells, increased CD21low B cells, impaired Th1 polarization, CD4+ T central memory exhaustion, and increased CD8+ T cell cytotoxicity. NK cell differentiation is defective, although cytotoxicity remains intact. Monocytes show persistent activation of inflammasome-related genes. These findings suggest the involvement of intact humoral immunity in regulating these processes and might indicate the need for early intervention to manage viral infections in CVID patients.

DOI: https://doi.org/10.1038/s41467-024-54732-x