bims-inflin 2025-04-06 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2025–04–06
six papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages.
Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.
Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis.
Signal-induced NLRP3 phase separation initiates inflammasome activation.
TPL2 kinase activity is required for Il1b transcription during LPS priming but dispensable for NLRP3 inflammasome activation.
Pathogen adaptation to lung metabolites.

Elife. 2025 Mar 27. pii: RP90107. [Epub ahead of print]12

Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages.

Marisa S Egan, Emily A O'Rourke, Shrawan Kumar Mageswaran, Biao Zuo, Inna Martynyuk, Tabitha Demissie, Emma N Hunter, Antonia R Bass, Yi-Wei Chang, Igor E Brodsky, Sunny Shin.

  Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.

Keywords:  Salmonella enterica serovar Typhimurium; human; human macrophages; immunology; infectious disease; inflammasomes; inflammation; microbiology; salmonella enterica serovar typhimurium

DOI:  https://doi.org/10.7554/eLife.90107
bioRxiv. 2025 Mar 14. pii: 2025.03.12.642696. [Epub ahead of print]

Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.

Anika M Arias, Dakota M Reinartz, Chloe Sairs, Sangeetha Senthil Kumar, Justin E Wilson.

Chronic inflammation and oral dysbiosis are common features of oral squamous cell carcinoma (OSCC). The commensal streptococci, S. anginosus, is increased in oral diseases including OSCC. Our previous work revealed that S. anginosus promotes inflammatory responses from macrophage cell lines, however the molecular mechanism by which S. anginosus interacts with macrophages to instigate this response remains to be investigated. Here, we expand on our previous findings by investigating the effects of S. anginosus infection of primary bone marrow derived macrophages (BMMs) and during in vivo infection. We found S. anginosus activated primary BMMs, which presented an enlarged cellular area, increased NF-κB activation and downstream inflammatory cytokines TNF⍰, IL-6 and IL-1β at 24 hours post infection. S. anginosus viability was dispensable for NF-κB activation, but essential for the induction of downstream inflammatory proteins and cytokines. S. anginosus persisted intracellularly within BMMs and induced the expression of inflammasome sensors AIM2, NLRC4 and NLRP3. Further, BMMs lacking the inflammasome adapter protein ASC ( Asc -/- ) had significantly diminished IL-1β production compared to wild type BMMs, indicating that S. anginosus activated the inflammasome. S. anginosus primarily triggered the inflammasome through NLRP3 as S. anginosus -infected Nlrp3 -/- BMMs and NLRP3 inhibitor (MCC950)-treated wild type BMMs displayed diminished IL-1β production compared to wild type controls. Lastly, S. anginosus -infected Asc -/- and Nlrp3 -/- mice displayed reduced weight loss compared to C57BL/6 mice. These overall findings indicate that S. anginosus replicates within macrophages and promotes a proinflammatory response in part through activation of the NLRP3 inflammasome. brief summary sentence: S. anginosus replicates intracellularly within macrophages and is sensed by the NLRP3 inflammasome to promote proinflammatory response.

DOI: https://doi.org/10.1101/2025.03.12.642696
Nat Commun. 2025 Apr 01. 16(1): 3125

Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis.

Gabriela Pessenda, Tiago R Ferreira, Andrea Paun, Juraj Kabat, Eduardo P Amaral, Olena Kamenyeva, Pedro Henrique Gazzinelli-Guimaraes, Shehan R Perera, Sundar Ganesan, Sang Hun Lee, David L Sacks.

In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2-/- mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL.

DOI: https://doi.org/10.1038/s41467-025-58360-x
Cell Res. 2025 Apr 01.

Signal-induced NLRP3 phase separation initiates inflammasome activation.

Gonglu Zou, Yuluan Tang, Jie Yang, Shuo Fu, Yuheng Li, Xuanyao Ren, Nanhai Zhou, Wenlong Zhao, Juyi Gao, Ziran Ruan, Zhengfan Jiang.

NLRP3 inflammasome is activated by diverse stimuli including infections, intracellular and environmental irritants. How NLRP3 senses these unrelated stimuli and what activates NLRP3 remain unknown. Here we report that signal-dependent NLRP3 phase separation initiated its activation, in which the palmitoyltransferase ZDHHC7-mediated tonic NLRP3 palmitoylation and an IDR region in the FISNA domain of NLRP3 play important roles. Moreover, three conserved hydrophobic residues in the IDR critically mediate multivalent weak interactions. NLRP3-activating stimuli including K+ efflux and NLRP3-interacting molecules imiquimod, palmitate, and cardiolipin all cause NLRP3 conformational change and induce its phase separation and activation in cells and/or in vitro. Surprisingly, amphiphilic molecules like di-alcohols used to inhibit biomolecular phase separation and chemotherapeutic drugs doxorubicin and paclitaxel activate NLRP3 independently of ZDHHC7 by directly inducing NLRP3 phase separation. Mechanistically, amphiphilic molecules decrease the solubility of both palmitoylated and non-palmitoylated NLRP3 to directly induce its phase separation and activation while NLRP3 palmitoylation reduces its solubility to some extent without activation. Therefore, ZDHHC7-mediated NLRP3 palmitoylation in resting cells licenses its activation by lowering the threshold for NLRP3 phase separation in response to any of the diverse stimuli whereas NLRP3 solubility-reducing molecules like di-alcohols and chemotherapeutic drugs activate NLRP3 directly. The signal-induced NLRP3 phase separation likely provides the simplest and most direct mechanistic basis for NLRP3 activation.

DOI: https://doi.org/10.1038/s41422-025-01096-6
Front Immunol. 2025 ;16 1496613

TPL2 kinase activity is required for Il1b transcription during LPS priming but dispensable for NLRP3 inflammasome activation.

Denise L Fahey, Niki Patel, Wendy T Watford.

  The NLRP3 inflammasome complex is an important mechanism for regulating the release of pro-inflammatory cytokines, IL-1β and IL-18, in response to harmful pathogens. Overproduction of pro-inflammatory cytokines has been linked to cryopyrin-associated periodic syndrome, arthritis, and other inflammatory conditions. It has been previously shown that tumor progression locus 2, a serine-threonine kinase, promotes IL-1β synthesis in response to LPS stimulation; however, whether TPL2 kinase activity is required during inflammasome priming to promote Il1b mRNA transcription and/or during inflammasome activation for IL-1β secretion remained unknown. In addition, whether elevated type I interferons, a consequence of either Tpl2 genetic ablation or inhibition of TPL2 kinase activity, decreases IL-1β expression or inflammasome function has not been explored. Using LPS-stimulated primary murine bone marrow-derived macrophages, we determined that TPL2 kinase activity is required for transcription of Il1b, but not Nlrp3, Il18, caspase-1 (Casp1), or gasdermin-D (Gsdmd) during inflammasome priming. Both Casp1 and Gsdmd mRNA synthesis decreased in the absence of type I interferon signaling, evidence of crosstalk between type I interferons and the inflammasome. Our results demonstrate that TPL2 kinase activity is differentially required for the expression of inflammasome precursor cytokines and components but is dispensable for inflammasome activation. These data provide the foundation for the further exploration of TPL2 kinase inhibitor as a potential therapeutic in inflammatory diseases.

Keywords:  IL-1b; NLRP3 inflammasome; TPL2; Tpl2 kinase; interferons; type I IFN

DOI:  https://doi.org/10.3389/fimmu.2025.1496613
Curr Opin Microbiol. 2025 Apr 02. pii: S1369-5274(25)00030-X. [Epub ahead of print]85 102608

Pathogen adaptation to lung metabolites.

Gaurav Kumar Lohia, Sebastián A Riquelme.

Opportunistic pathogens like Pseudomonas aeruginosa and Staphylococcus aureus rapidly adapt to the dynamic metabolic landscape of the respiratory mucosa during infection. Host phagocytes recognize these pathogens and trigger metabolic reprogramming, releasing immunometabolites such as succinate and itaconate. P. aeruginosa preferentially consumes succinate as a carbon source to enhance planktonic growth. In response to itaconate-induced membrane stress, it forms protective biofilms, allowing bacterial survival despite host defenses. Additionally, host ketone bodies support microbial communities that are less immunostimulatory and better tolerated by the lung. Similarly, S. aureus responds to itaconate by forming biofilms, aiding colonization in glucose-limited airways. In this milieu, S. aureus consumes proline, linking its survival with the metabolic activity of proline-producing fibroblasts. Here, we will review the competence of both P. aeruginosa and S. aureus to hijack host metabolic pathways, underscoring pathogen metabolic plasticity as an essential strategy to thrive in the human lung.

DOI: https://doi.org/10.1016/j.mib.2025.102608