bims-inflin 2025-01-12 papers

Immunol Rev. 2025 Jan;329(1): e13436

MAP Kinase Signaling at the Crossroads of Inflammasome Activation.

Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how Bacillus anthracis lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.

Keywords: JNK; MAP kinase; TAK1; inflammasome; inflammation; p38; pyroptosis

DOI: https://doi.org/10.1111/imr.13436

PLoS Negl Trop Dis. 2025 Jan 07. 19(1): e0012763

Pharmacological inhibition of key metabolic pathways attenuates Leishmania spp infection in macrophages.

Elaine Carvalho de Oliveira, Rafael Tibúrcio, Gabriela Duarte, Amanda Lago, Léon de Melo, Sara Nunes, Gustavo Gastão Davanzo, Ana Júlia Martins, Bruno Vinagre Ribeiro, Deborah Mothé, Juliana B P Menezes, Patrícia Veras, Natalia Tavares, Pedro M Moraes-Vieira, Cláudia Ida Brodskyn.

Macrophages represent a fundamental component of the innate immune system that play a critical role in detecting and responding to pathogens as well as danger signals. Leishmania spp. infections lead to a notable alteration in macrophage metabolism, whereby infected cells display heightened energy metabolism that is linked to the integrity of host mitochondria. However, little is known about how different species of Leishmania manipulate host metabolism. Here, we demonstrate that despite differences in their mechanisms for evading host immune responses, L. amazonensis and L. braziliensis induce comparable disruptions in key metabolic pathways. We found that infected macrophages exhibited an overall elevation in energy metabolism regardless of the parasite strain, evidenced by the elevation in glycolysis and oxygen consumption rates, along with increased proton leak and decreased ATP production. We also analyzed the effects of both Leishmania spp. strain infection on mitochondria function, further revealing that infected cells display heightened mitochondrial mass and membrane potential. To investigate the metabolic pathways required for Leishmania amastigotes to persist in BMDMs, we pre-treated cells with small molecule drugs that target major metabolic pathways, revealing that perturbations in several metabolic processes affected parasite survival in a strain-independent manner. Treatments with inhibitors of the oxidative phosphorylation and glycolysis substantially reduced parasite loads. Collectively, our findings suggest that L.amazonensis and L.braziliensis exploit host cell metabolic pathways similarly to survive in macrophages.

DOI: https://doi.org/10.1371/journal.pntd.0012763

Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01523-7. [Epub ahead of print]44(1): 115172

Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.

Juliana Escher Toller-Kawahisa, Paula Ramos Viacava, Eva Margareta Palsson-McDermott, Daniele Carvalho Nascimento, Mariana Patricia Cervantes-Silva, Shane Myles O'Carroll, Alessia Zotta, Luis Eduardo Alves Damasceno, Gabriel Azevedo Públio, Pedro Forti, João Paulo Mesquita Luiz, Bruno Marcel Silva de Melo, Timna Varela Martins, Vitor Marcel Faça, Annie Curtis, Thiago Mattar Cunha, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.

Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.

Keywords: CP: Immunology; CP: Metabolism; IL-10; PKM2; adenosine; macrophage; mitochondria dynamics

DOI: https://doi.org/10.1016/j.celrep.2024.115172

Cell Commun Signal. 2025 Jan 06. 23(1): 6

Helicobacter pylori infection promotes M1 macrophage polarization and gastric inflammation by activation of NLRP3 inflammasome via TNF/TNFR1 axis.

Xiao Fei, Sihai Chen, Leyan Li, Xinbo Xu, Huan Wang, Huajing Ke, Cong He, Chuan Xie, Xidong Wu, Jianping Liu, Yong Xie, Nonghua Lu, Yin Zhu, Nianshuang Li.

BACKGROUND: Macrophages play a crucial role in chronic gastritis induced by the pathogenic Helicobacter pylori (H. pylori) infection. NLRP3 inflammasome has emerged as an important component of inflammatory processes. However, the molecular mechanism by which H. pylori infection drives NLRP3 inflammasome and macrophages activation remains unclear.
METHODS: Human gastritis tissues were collected for clinical significance of NLRP3. Infection with H. pylori was performed using in vitro and in vivo models. Bone marrow-derived macrophages (BMDMs) from wild-type (WT), Nlrp3-knockout (KO) and Tnfr1-KO mice were infected with H. pylori. Western blotting, qRT-PCR, immunofluorescence, immunohistochemistry and ELISA were utilized for functional and mechanistic studies.
RESULTS: Single-cell RNA sequencing (ScRNA-seq) analysis of human gastric tissues, followed by validation, indicated that NLRP3 was primarily expressed in myeloid cells and was significantly increased in H. pylori-positive gastritis compared to H. pylori-negative gastritis. Infection with PMSS1 and NCTC11637 H. pylori strains induced NLRP3 inflammasome activation in vitro (THP1 cells) and in the insulin-gastrin (INS-GAS) transgenic mouse model. Deletion of NLRP3 in BMDMs showed marked inhibition of H. pylori-induced M1 macrophage polarization. Furthermore, NLRP3 inflammasome activation upon TNFα, or H. pylori stimulation, was partially blocked by TNFα/TNFR1 signaling inhibitors. Deletion of TNFR1 in BMDMs significantly impaired NLRP3 inflammasome activation and M1 macrophages induced by H. pylori.
CONCLUSION: This study revealed that the activation of NLRP3 inflammasome, regulated by the TNF/TNFR1 signaling axis, is a key regulator of H. pylori-induced M1 macrophage activation and gastritis.

Keywords: H. pylori ; Gastritis; Macrophage; NLRP3 inflammasome; TNF/TNFR1 axis

DOI: https://doi.org/10.1186/s12964-024-02017-7

Cytokine. 2025 Jan 06. pii: S1043-4666(24)00356-9. [Epub ahead of print]186 156852

Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.

Shawna Yadav, Anusha Prasannan, Kaliyamurthi Venkatachalam, Ambika Binesh.

Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.

Keywords: Interleukin-6; Interleulin-1β; Macrophage polarization and inflammation; Macrophages; Metabolic stress

DOI: https://doi.org/10.1016/j.cyto.2024.156852