bims-inflin 2024-05-12 papers

Issue of 2024‒05‒12
three papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Microbes Infect. 2024 May 07. pii: S1286-4579(24)00081-9. [Epub ahead of print] 105351

Impact of IL-1β on lung pathology caused by Mycobacterium abscessus infection and its association with IL-17 production.

Jae-Hun Ahn, Do-Hyeon Jung, Dong-Yeon Kim, Tae-Sung Lee, Yeong-Jun Kim, Yun-Ji Lee, In-Su Seo, Wan-Gyu Kim, Young Jin Cho, Sung Jae Shin, Jong-Hwan Park.

Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex that triggers IL-1β maturation and pyroptosis through the cleavage of caspase-1. In this study, we investigated the roles of NLRP3 and IL-1β in the host's defense against MAB. The IL-1β production by MAB was completely abolished in NLRP3, but not NLRC4, deficient macrophages. The NLRP3 inflammasome components, which are ASC and caspase-1 were also found to be essential for IL-1β production in response to MAB. NLRP3 and IL-1β deficiency did not affect the intracellular growth of MAB in macrophages, and the bacterial burden in lungs of NLRP3- and IL-1β-deficient mice was also comparable to the burden observed in WT mice. In contrast, IL-1β deficiency ameliorated lung pathology in MAB-infected mice. Notably, the lung homogenates of IL-1β-deficient mice had reduced levels of IL-17, but not IFN-γ and IL-4 when compared with WT counterparts. Furthermore, in vitro co-culture analysis showed that IL-1β signaling was essential for IL-17 production in response to MAB. Finally, we observed that the anti-IL-17 antibody administration moderately mitigated MAB-induced lung pathology. These findings indicated that IL-1β production contribute to MAB-induced lung pathology via the elevation of IL-17 production.

Keywords: IL-17; IL-1β; Mycobacterium abscessus; NLRP3 inflammasome; pulmonary inflammation

DOI: https://doi.org/10.1016/j.micinf.2024.105351

Front Immunol. 2024 ;15 1298275

The non-pathogenic protozoon Leishmania tarentolae interferes with the activation of NLRP3 inflammasome in human cells: new perspectives in the control of inflammation.

Francesca La Rosa, Ilaria Varotto-Boccazzi, Marina Saresella, Ivana Marventano, Giulia Maria Cattaneo, Ambra Hernis, Federica Piancone, Domenico Otranto, Sara Epis, Claudio Bandi, Mario Clerici.

Background: Innate immune responses against infectious agents can act as triggers of inflammatory diseases. On the other hand, various pathogens have developed mechanisms for the evasion of the immune response, based on an inhibition of innate immunity and inflammatory responses. Inflammatory diseases could thus be controlled through the administration of pathogens or pathogen-derived molecules, capable of interfering with the mechanisms at the basis of inflammation. In this framework, the NLRP3 inflammasome is an important component in innate antimicrobial responses and a major player in the inflammatory disease. Parasites of the genus Leishmania are master manipulators of innate immune mechanisms, and different species have been shown to inhibit inflammasome formation. However, the exploitation of pathogenic Leishmania species as blockers of NLRP3-based inflammatory diseases poses safety concerns.Methods: To circumvent safety issues associated with pathogenic parasites, we focused on Leishmania tarentolae, a species of Leishmania that is not infectious to humans. Because NLRP3 typically develops in macrophages, in response to the detection and engulfment microorganisms, we performed our experiments on a monocyte-macrophage cell line (THP-1), either wild type or knockout for ASC, a key component of NLRP3 formation, with determination of cytokines and other markers of inflammation.
Results: L. tarentolae was shown to possess the capability of dampening the formation of NLRP3 inflammasome and the consequent expression of pro-inflammatory molecules, with minor differences compared to effects of pathogenic Leishmania species.
Conclusion: The non-pathogenic L. tarentolae appears a promising pro-biotic microbe with anti-inflammatory properties or a source of immune modulating cellular fractions or molecules, capable of interfering with the formation of the NLRP3 inflammasome.

Keywords: Leishmania tarentolae; NLRP3; immunity responses; inflammasome pathway; inflammation

DOI: https://doi.org/10.3389/fimmu.2024.1298275

Int J Nanomedicine. 2024 ;19 4007-4019

Staphylococcus Aureus Membrane Vesicles Kill Tumor Cells Through a Caspase-1-Dependent Pyroptosis Pathway.

Mengyang Li, Yuting Wang, He Liu, Xiaonan Huang, Huagang Peng, Yi Yang, Zhen Hu, Jianxiong Dou, Chuan Xiao, Juan Chen, Weilong Shang, Xiancai Rao.

Introduction: Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated.Methods: MVs of Staphylococcus aureus USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2-MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor.
Results: The vesicular particles of S. aureus USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 μg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2-MVs (R2 = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10-3 μg. Antares2-MVs can directly target tumor tissues in vivo, and 20 μg/mL Antares2-MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo.
Conclusion: S. aureus MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment.

Keywords: Antares2; GSDMD; Staphylococcus aureus; cancer therapy; caspase-1; membrane vesicles; pyroptosis

DOI: https://doi.org/10.2147/IJN.S455158