bims-nocaut 2024-04-14 papers

Issue of 2024–04–14
three papers selected by
Quentin Frenger, University of Strasbourg

Front Immunol. 2024 ;15 1367048

Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.

Zhenghui Yang, Xinyi Wang, Tianxiang Dong, Wei-Jia Zhao, Hongbin Li.

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect.
Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics.
Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time.
Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.

Keywords: Candida glabrata; LC3-associated phagocytosis; autophagy; glucocorticoids; macrophage

DOI: https://doi.org/10.3389/fimmu.2024.1367048

J Immunol. 2024 Apr 12. pii: ji2300290. [Epub ahead of print]

Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity.

Alina K Lorant, Anna E Yoshida, Emily A Gilbertson, Talyn Chu, Caroline Stefani, Mridu Acharya, Jessica A Hamerman, Adam Lacy-Hulbert.

Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and β3-knockout pDCs produce more IFN-I and inflammatory cytokines than controls when stimulated through TLR7 and TLR9 in vitro and in vivo. Increased cytokine production was associated with delayed acidification of endosomes containing TLR ligands, reduced LC3 conjugation, and increased TLR signaling. This dysregulated TLR signaling results in activation of B cells and promotes germinal center (GC) B cell and plasma cell expansion. Furthermore, in a mouse model of TLR7-driven lupus-like disease, deletion of αvβ3 from pDCs causes accelerated autoantibody production and pathology. We therefore identify a pDC-intrinsic role for αvβ3 in regulating TLR signaling and preventing activation of autoreactive B cells. Because αvβ3 serves as a receptor for apoptotic cells and cell debris, we hypothesize that this regulatory mechanism provides important contextual cues to pDCs and functions to limit responses to self-derived nucleic acids.

DOI: https://doi.org/10.4049/jimmunol.2300290

Int J Oncol. 2024 Jun;pii: 57. [Epub ahead of print]64(6):

Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review).

Giulia Tedesco, Manuela Santarosa, Roberta Maestro.

Autophagy is a conserved catabolic process that controls organelle quality, removes misfolded or abnormally aggregated proteins and is part of the defense mechanisms against intracellular pathogens. Autophagy contributes to the suppression of tumor initiation by promoting genome stability, cellular integrity, redox balance and proteostasis. On the other hand, once a tumor is established, autophagy can support cancer cell survival and promote epithelial‑to‑mesenchymal transition. A growing number of molecules involved in autophagy have been identified. In addition to their key canonical activity, several of these molecules, such as ATG5, ATG12 and Beclin‑1, also exert autophagy‑independent functions in a variety of biological processes. The present review aimed to summarize autophagy‑independent functions of molecules of the autophagy machinery and how the activity of these molecules can influence signaling pathways that are deregulated in cancer progression.

Keywords: autophagy; autophagy‑independent; cancer; cancer progression; cell death; genome instability; metastasis; proliferation; survival

DOI: https://doi.org/10.3892/ijo.2024.5645