bims-inflin 2025-04-27 papers

on Inflammasome and infection

Issue of 2025–04–27
eleven papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.
P62 inhibits IL-1β release during Salmonella Typhimurium infection of macrophages.
Salmonella-NLRP3 Inflammasome Crosstalk: Host Defense Activation Versus Bacterial Immune Evasion Strategies.
A host-pathogen metabolic synchrony that facilitates disease tolerance.
Evolutionary and functional analysis of caspase-8 and ASC interactions to drive lytic cell death, PANoptosis.
Mechanism and role of H. pylori CagA-induced NLRP3 inflammasome in gastric cancer immune cell infiltration.
Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.
Inflammasomopathies: mechanisms and disease signatures.
Mitochondrial DNA signals driving immune responses: Why, How, Where?
Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

mBio. 2025 Apr 24. e0081825

NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.

Mateusz Szczerba, Akshaya Ganesh, María Luisa Gil-Marqués, Volker Briken, Marcia B Goldberg.

  The NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and non-canonical NLRP3 inflammasome activation after infection with gram-negative bacteria. Here, we generated a series of defined NLRP11 deletion mutants to further analyze the role of NLRP11 in NLRP3 inflammasome activation. Like the complete NLRP11 deletion mutant (NLRP11-/-), the NLRP11 mutant lacking the NAIP, C2TA, HET-E, and TP1 (NACHT) and leucine-rich repeat (LRR) domains (NLRP11∆N_LRR) showed reduced activation of the canonical NLRP3 inflammasome, whereas a pyrin domain mutant (NLRP11∆PYD) had no effect on NLRP3 activation. The NLRP11-/- and NLRP11∆N_LRR mutants, but not the NLRP11∆PYD mutant, also displayed reduced activation of caspase-4 during infection with the intracytosolic, gram-negative pathogen Shigella flexneri. We found that the human-adapted, acid-fast pathogen Mycobacterium tuberculosis and the opportunistic pathogen Mycobacterium kansasii both activate the non-canonical NLRP11 inflammasome in a caspase-4/caspase-5-dependent pathway. In conclusion, we show that NLRP11 functions in the non-canonical caspase-4/caspase-5 inflammasome activation pathway and the canonical NLRP3 inflammasome pathway and that NLRP11 is required for full recognition of mycobacteria by each of these pathways. Our work extends the spectrum of bacterial pathogen recognition by the non-canonical NLRP11-caspase4/caspase-5 pathway beyond gram-negative bacteria.IMPORTANCEThe activation of inflammasome complexes plays a crucial role in intracellular pathogen detection. NLRP11 and caspase-4 are essential for recognizing lipopolysaccharide (LPS), a molecule found in gram-negative bacteria such as the human pathogens Shigella spp., which activate both canonical NLRP3 and non-canonical inflammasome pathways. Through a series of deletion mutants, we demonstrate that the NACHT and LRR domains of NLRP11, but not its pyrin domain, are critical for detection of S. flexneri. Notably, our research reveals that the acid-fast bacterium M. tuberculosis is also detected by NLRP11 and caspase-4, despite not producing LPS. These findings significantly expand the range of pathogens recognized by NLRP11 and caspase-4 to now include acid-fast bacteria that do not contain LPS and underscore the versatility of these innate immune components in pathogen detection.

Keywords:  NLRP11; NLRP3; inflammasomes; innate immunity; macrophages; mycobacteria

DOI:  https://doi.org/10.1128/mbio.00818-25
Front Cell Infect Microbiol. 2025 ;15 1495567

P62 inhibits IL-1β release during Salmonella Typhimurium infection of macrophages.

Nina Judith Hos, Julia Fischer, Ambika M V Murthy, Zahra Hejazi, Martin Krönke, Deniz Hos, Nirmal Robinson.

  Macrophages are critical for the innate immune defense against the facultative intracellular Gram-negative bacterium Salmo\nella enterica serovar Typhimurium. Following phagocytosis by macrophages, S. Typhimurium activates cytoplasmic NLRC3 and NLRP4 inflammasomes, which share the adaptor ASC, resulting in the secretion of the pro-inflammatory cytokine IL-1β. To prevent excessive inflammation and tissue damage, inflammatory signaling pathways are tightly controlled. Recently, autophagy has been suggested to limit inflammation by targeting activated inflammasomes for autophagic degradation. However, the importance of the autophagic adaptor Sequestome-1 (hereafter, p62) for regulating inflammasome activation remains poorly understood. We report here that p62 restricts inflammasome availability and subsequent IL-1β secretion in macrophages infected with S. Typhimurium by targeting the inflammasome adaptor ASC for autophagic degradation. Importantly, loss of p62 resulted in impaired autophagy and increased IL-1β secretion, as well as IL-10 and IFN-β release. In summary, our results demonstrate a novel role for p62 in inducing autophagy and balancing major pro- and anti-inflammatory signaling pathways to prevent excessive inflammation during S. Typhimurium infection of macrophages.

Keywords:  ASC; IFN-I; IFN-β; IL-10; IL-1β; autophagy; inflammasome; p62

DOI:  https://doi.org/10.3389/fcimb.2025.1495567
J Inflamm Res. 2025 ;18 5133-5148

Salmonella-NLRP3 Inflammasome Crosstalk: Host Defense Activation Versus Bacterial Immune Evasion Strategies.

Yuxuan Li, Ying Xu, Cheng Jin, Jiayi Qiu, Xinan Jiao, Zhiming Pan, Yaxin Guo.

  The innate immune system plays a crucial role in defending against Salmonella infection. Inflammasomes are macromolecular complexes that assemble in response to the recognition of pathogen- or danger-associated molecular patterns. These complexes serve as signaling platforms for the activation of inflammatory Caspases, which subsequently triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. This process also initiates pyroptosis, a highly inflammatory form of programmed cell death characterized by lytic cell lysis. Salmonella are intracellular pathogens that proliferate within epithelial cells and macrophages, posing a significant public health risk in both developed and developing countries. During Salmonella infection, the canonical NLRP3 and NLRC4 inflammasome, as well as non-canonical inflammasome, are activated. Unlike NLRC4 and non-canonical inflammasomes, which play crucial roles during intestinal infection phases, the role of NLRP3 inflammasome in resisting Salmonella infection demonstrates a higher degree of complexity and uncertainty. Nonetheless, the activation of NLRP3 inflammasome, along with the downstream innate and adaptive responses, form a robust host immune barrier against potential pathogens. Therefore, successful pathogens must evolve multiple mechanisms to circumvent or counteract these immune barriers. Here we review and discuss the mechanisms of NLRP3 inflammasome activation triggered by intracellular Salmonella, as well as the multiple strategies employed by Salmonella to avoid or delay NLRP3 inflammasome activation. A deeper understanding of how NLRP3 inflammasomes recognize Salmonella and how pathogens evade NLRP3 activation has the potential to facilitate the development of novel prevention and control measures for Salmonella infection.

Keywords:  NLRP3; Salmonella; caspases; immune evasion; inflammasome

DOI:  https://doi.org/10.2147/JIR.S519902
Nat Commun. 2025 Apr 19. 16(1): 3729

A host-pathogen metabolic synchrony that facilitates disease tolerance.

Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.

Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.

DOI: https://doi.org/10.1038/s41467-025-59134-1
Mol Biol Evol. 2025 Apr 25. pii: msaf096. [Epub ahead of print]

Evolutionary and functional analysis of caspase-8 and ASC interactions to drive lytic cell death, PANoptosis.

Sivakumar Prasanth Kumar, Eswar Kumar Nadendla, R K Subbarao Malireddi, Syed Asfarul Haque, Raghvendra Mall, Andrew F Neuwald, Thirumala-Devi Kanneganti.

  Caspases are evolutionarily conserved proteins essential for driving cell death in development and host defense. Caspase-8, a key member of the caspase family, is implicated in apoptosis, a non-lytic form of cell death, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multi-protein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate this caspase-8-containing PANoptosome complex to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8's complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among sub-family members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8's death effector domain and ASC's pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.

Keywords:  ASC; Apoptosis; Arms race; Caspases; Co-evolution; Crosstalk; DED filament; Death domain superfamily; Death fold; Evolution; Helical assembly; Host-pathogen interactions; Inflammasome; Inflammation; Inflammatory response; Innate immunity; Necroptosis; PANoptosis; PANoptosome; PYCARD; Pyroptosis; cell death

DOI:  https://doi.org/10.1093/molbev/msaf096
Sci Rep. 2025 Apr 24. 15(1): 14335

Mechanism and role of H. pylori CagA-induced NLRP3 inflammasome in gastric cancer immune cell infiltration.

Chuandan Wan, Ping Wang, Yeqiong Xu, Yanping Zhu, Huanhuan Chen, Xuexian Cao, Yulan Gu.

  The high incidence of gastric cancer in China is strongly associated with widespread Helicobacter pylori infection. While the bacterium's role in gastric cancer initiation and progression is well-established, the precise molecular mechanisms remain incompletely characterized. Current clinical challenges include limited early detection methods and poor therapeutic efficacy in advanced stages. Immune checkpoint inhibitors have shown clinical benefits in subsets of patients; however, many exhibit primary resistance or acquire secondary resistance, though the mechanisms underlying this resistance remain poorly understood. Emerging evidence suggests that H.pylori infection may remodel the tumor microenvironment, thereby influencing gastric cancer pathogenesis, progression, and therapeutic response. This study investigates the CagA virulence factor-mediated signal-transduction pathway during H.pylori infection, elucidating its role in NLRP3 inflammasome activation and subsequent pathological modulation of gastric epithelial cells. We further analyze correlations between NLRP3 expression and clinicopathological features, evaluating its prognostic value in predicting clinical outcomes. Additionally, we examine how this signaling axis regulates immune cell infiltration and modulates molecular pathology within the tumor immune microenvironment, laying a foundation for novel diagnostic and immunotherapeutic strategies.

Keywords:   Helicobacter pylori ; Gastric cancer; Immune infiltration; NLRP3 inflammasome; Prognosis

DOI:  https://doi.org/10.1038/s41598-025-98301-8
Cell Rep. 2025 Apr 22. pii: S2211-1247(25)00372-9. [Epub ahead of print]44(5): 115601

Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.

Margarida C Gomes, Dominik Brokatzky, Serge Mostowy.

  Shigella is an important human pathogen that has no licensed vaccine. Despite decades of seminal work suggesting that its pathogenicity relies on inflammatory cell death of macrophages, the in vivo role of macrophages in controlling Shigella infection remains poorly understood. Here, we use a zebrafish model of innate immune training to investigate the antibacterial role of macrophages following a non-lethal Shigella infection. We found that macrophages are crucial for zebrafish larvae survival during secondary Shigella infection. Consistent with signatures of trained immunity, we demonstrate that bacteria are cleared during training and that protection is independent of the secondary infection site. We show that following Shigella training, macrophages have altered mono- and tri-methylation on lysine 4 in histone 3 (H3K4me1/me3) deposition and shift toward a pro-inflammatory state, characterized by increased tumor necrosis factor alpha (TNF-α) expression and antibacterial reactive oxygen species (ROS) production. We conclude that macrophages are epigenetically reprogrammed by Shigella infection to enhance pro-inflammatory and protective responses.

Keywords:  CP: Immunology; CP: Microbiology; Shigella; infection biology; macrophages; trained immunity; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.115601
Trends Immunol. 2025 Apr 21. pii: S1471-4906(25)00082-1. [Epub ahead of print]

Inflammasomopathies: mechanisms and disease signatures.

Sara Cahill, Fiachra Humphries.

  Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'inflammasomopathies'. Recently, molecular interrogation of these diseases revealed several distinctions at the level of the tissue affected, the inflammatory mediators that drive disease progression, and the contribution of programmed cell death. In this review we discuss key emerging differences across inflammasomopathies and the distinct inflammatory patterns seen in patients. We discuss how programmed cell death influences the progression of inflammasomopathies and the role of plasma membrane rupture. Understanding the molecular disease signatures across inflammasomopathies provides crucial insights into identifying and treating the underlying disease and opens new avenues for therapeutic interventions.

Keywords:  NLRC4; NLRP3; gain of function; inflammasomopathies; plasma membrane rupture; pyrin, NLRP1; pyroptosis

DOI:  https://doi.org/10.1016/j.it.2025.03.008
Cell Commun Signal. 2025 Apr 22. 23(1): 192

Mitochondrial DNA signals driving immune responses: Why, How, Where?

Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.

  There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s12964-025-02042-0
Immunology. 2025 Apr 23.

Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.

Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Larissa Menezes Dos Reis, Isabella Bonilha de Oliveira, José Luís Fachi, João Victor Virgilio-da-Silva, Marcelo Rodrigues Berçot, Mariane Font Fernandes, Sarah de Oliveira, Nathalia Vitoria Pereira Araujo, Guilherme Ribeiro, Gisele de Castro, Webster Leonardo Guimarães Costa, Adriana Leandra Santoro, Gabriela Flavia Rodrigues-Luiz, Helison Rafael P do Carmo, Ikaro Breder, Marcelo A Mori, Alessandro S Farias, Daniel Martins-de-Souza, Joseph W Guarnieri, Douglas C Wallace, Marco Aurélio Ramirez Vinolo, José Luiz Proença-Módena, Afshin Beheshti, Andrei C Sposito, Pedro M Moraes-Vieira.

  Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA-derived acetyl-CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL-6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID-19.

Keywords:  COVID‐19; inflammation; innate immunity; monocyte; obesity

DOI:  https://doi.org/10.1111/imm.13934
Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4