bims-inflin 2025-06-01 papers

on Inflammasome and infection

Issue of 2025–06–01
seven papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Transcriptomic and Immunopathological Profiles of Inflammasomes in Different Clinical Forms of American Cutaneous Leishmaniasis.
Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.
ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner Gasdermin D.
SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway.
A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.
Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani.
Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation.

Microorganisms. 2025 Apr 24. pii: 980. [Epub ahead of print]13(5):

Transcriptomic and Immunopathological Profiles of Inflammasomes in Different Clinical Forms of American Cutaneous Leishmaniasis.

Larissa Dos Santos Alcântara, Marliane Batista Campos, Ana Carolina Stocco Lima, Alessandra Pontillo, Kamilla Batista da Silva Souza, Aurea Favero Ferreira, Cristina Pires Camargo, Sueli Mieko Oba-Shinjo, Márcia Dalastra Laurenti, Carlos Eduardo Pereira Corbett, Vania L R da Matta, Helder Nakaya, Fernando T Silveira, Claudia Maria de Castro Gomes.

  American cutaneous leishmaniasis (ACL), caused by Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis, presents a wide spectrum of clinical and immunopathological manifestations, ranging from localized cutaneous leishmaniasis (LCL) to severe forms like anergic diffuse cutaneous (ADCL) and mucocutaneous leishmaniasis (MCL). Despite evidence of the immune response's complexity, the role of inflammasomes in disease severity and parasite persistence remains unclear. We investigated the transcriptomic and immunopathological profiles of inflammasome components in patient lesions across the clinical spectrum. Genes such as NLRP3, AIM2, NLRP12, NLRC4, CASP1, CASP5, GSDMD, and IL1B and all evaluated proteins, showed higher expression in ACL compared to healthy controls. Distinct inflammasome activation patterns were observed: MCL, the hyperreactive form, showed elevated NLRP3, AIM2, and IL-1β, indicating an intensified inflammatory environment. ADCL, the hyporeactive form, displayed increased NLRP12 and NLRC4 expression with reduced GSDMD. Localized forms showed transitional profiles, highlighting ACL's multifactorial pathogenesis. These findings advance our understanding of inflammasome mechanisms in ACL, identifying potential therapeutic targets to modulate inflammation and improve management.

Keywords:  Leishmania (Leishmania) amazonensis; Leishmania (Viannia) braziliensis; american cutaneous leishmaniasis; immunopathological profiles; inflammasomes; transcriptomic

DOI:  https://doi.org/10.3390/microorganisms13050980
Nat Commun. 2025 May 27. 16(1): 4887

Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.

Elvira Boršić, Taja Železnik Ramuta, Sara Orehek, Mateja Erdani Kreft, Matthias Geyer, Roman Jerala, Iva Hafner-Bratkovič.

NLRP3 is a pattern recognition receptor forming an inflammasome in response to diverse pathogen and self-derived triggers, but molecular insights on NLRP3 activation are still lacking. Here, we drive ectopic NLRP3 to different subcellular locations in NLRP3-deficient macrophages to map the spatial activation profile of NLRP3, and find that NLRP3 variants enriched at the organellar membranes respond to canonical triggers similarly to wild-type NLRP3; however, unlike wild-type, these NLRP3 variants can be activated even in the absence of the polybasic phospholipid-binding segment. Mechanistically, membrane or protein scaffolds mediate NLRP3 clustering, which leads to the unfastening of the inactive NACHT domain conformation preceding the activated NLRP3 oligomer formation. Our data thus suggest that scaffold-promoted clustering is an important step in NLRP3 activation, enabling NLRP3 to sense distinct activator-induced cellular anomalies exhibited via lipid or protein assemblies, thereby establishing NLRP3 as the master sensor of perturbations in cell homeostasis.

DOI: https://doi.org/10.1038/s41467-025-60277-4
Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2502798122

ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner Gasdermin D.

Nilam Bhandari, Ashutosh Prince, Mariam R Khan, C Alicia Traughber, Kalash Neupane, Shuhui W Lorkowski, Gregory Brubaker, Elif G Ertugral, Chandrasekhar R Kothapalli, George R Dubyak, Jonathan D Smith, Kailash Gulshan.

  Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis, with symptoms including pruritus, pancreatitis, fat malabsorption, intestinal inflammation, and failure to thrive. High-throughput studies showed interconnection between ATP8B1 and phosphoinositide (PIPs), but the mechanism linking ATP8B1, lipid metabolism, and inflammation remains unclear. Atp8b1G308V/G308V mouse model, unbiased RNAseq, high-resolution-stimulation emission depltion (STED)-microscopy, and Crispr-Cas9 generated ATP8B1-/- knockouts in hepatocytes/monocytes/macrophages were used to determine role of ATP8B1 in phosphatidylinositol,4-5-bisphosphate (PIP2) trafficking and inflammation. Human ATP8B1, purified from Sf9 insect cells and reconstituted in proteoliposomes, was used to test cell-free PIP2 flip. Various in-vitro techniques were used for testing direct interaction between PIP2 and ATP8B1. ATP8B1 maintains PIP2 at the inner leaflet of plasma membrane (PM). ATP8B1 flips PIP2 in cells, without altering flip of PE or bulk-endocytosis. ATP8b1 flips PIP2 in a cell-free system. ATP8B1 deletion promotes bile-salt-mediated cholesterol extraction from hepatocytes in a PIP2-dependent manner. PIP2 directly binds to the P-loop of ATP8B1. Unbiased RNAseq showed upregulation of inflammatory cytokines in ATP8b1-/- immune cells. ATP8B1-/- monocytes/macrophages showed aberrant lipopolysaccharide (LPS)-induced cleavage of GSDMD, formation of GSDMD pores, and interleukin-1beta (IL1β) release. Inflammation-resolving efferocytosis was impaired in ATP8B1-/- macrophages. Biophysical properties of PM were altered in ATP8b1-/- cells, with the mechanism being disrupted localization of PIP2. Atp8b1G308V/G308V mice exposed to LPS showed higher plasma IL1β and lower survival rates vs. WT mice. ATP8B1 maintains PIP2 at the inner leaflet of PM. ATP8b1 directly flips and binds PIP2. ATP8B1 regulates LPS-induced GsdmD cleavage, formation of GsdmD pores, IL1β release, and mortality in mice.

Keywords:  ATP8b1; Gasdermin D; PFIC1; PIP2; inflammasome

DOI:  https://doi.org/10.1073/pnas.2502798122
mBio. 2025 May 28. e0042525

SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway.

Hua Yang, Pak-Hin Hinson Cheung, Li Wu.

  Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. While SAMHD1 is known to promote spontaneous apoptosis, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unclear. In this study, we identify a novel mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway. We demonstrate that SAMHD1 enhances apoptosis induced by HIV-1 infection in dividing monocytic THP-1 and U937 cell lines, but not in differentiated macrophage-like cells. Mechanistically, SAMHD1 expression reduces mitochondrial membrane potential and promotes cytochrome c release in HIV-1-infected THP-1 cells, thereby augmenting the mitochondrial apoptotic pathway. Furthermore, SAMHD1-enhanced apoptosis is linked to elevated levels of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells, which contributes to enhanced apoptosis during HIV-1 infection. These findings reveal a previously unrecognized regulatory role of SAMHD1 in amplifying HIV-1-induced apoptosis in monocytic cells, highlighting its involvement in the mitochondrial apoptotic pathway.IMPORTANCESterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, lowers intracellular dNTP levels and restricts HIV-1 replication in non-dividing cells. HIV-1 infection induces cell death mainly through apoptosis. While we have shown that endogenous SAMHD1 enhances spontaneous apoptosis in monocytic cells, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unknown. In this study, we aim to bridge this knowledge gap by investigating the functional significance of SAMHD1 in regulating apoptosis during HIV-1 infection of immune cells. Our findings reveal a novel mechanism whereby SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. This suggests a previously unrecognized role of SAMHD1 in modulating cellular responses to HIV-1 infection.

Keywords:  BCL-2-interacting killer; HIV-1 infection; SAMHD1; THP-1 cells; apoptosis; cytochrome c; mitochondrial membrane potential; mitochondrial pathway; monocytic cells

DOI:  https://doi.org/10.1128/mbio.00425-25
Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2420245122

A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.

Shufen Li, Hao Li, Zhenxing Zhou, Meidi Ye, Yifei Wang, Wenqin Li, Zhenqiong Guan, Zihan Guan, Chongtao Zhang, Yulan Zhang, Wei Liu, Ke Peng.

  Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs-RIPK3 condensate inhibited RIPK3-mediated apoptosis and promoted viral replication. Infection with an SFTSV NSs mutant virus not forming NSs condensate triggered pronounced apoptosis resulting in reduced viral replication and decreased fatality in vivo. Blocking SFTSV-triggered necroptosis through depletion of MLKL or treatment with a RIPK3-kinase inhibitor reduced viral inflammatory pathogenesis and fatality in vivo. In contrast, blocking SFTSV-triggered apoptosis through depletion of RIPK3 resulted in enhanced viral replication and increased fatality in vivo. The virus-triggered necroptosis correlated with severe inflammatory pathogenesis and lethality in virus-infected patients. The NSs-RIPK3 condensate may represent a necroptosis activation mechanism that promotes viral pathogenesis.

Keywords:  NSs; RIPK3; cell death; inflammatory pathogenesis; viral necrosome

DOI:  https://doi.org/10.1073/pnas.2420245122
Elife. 2025 May 27. pii: RP102857. [Epub ahead of print]14

Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani.

Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee.

  The management of Leishmania donovani (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.

Keywords:  LDL-cholesterol; cell biology; clinical Leishmania donovani isolates; drug unresponsiveness; infectious disease; lipid droplets; microbiology; mouse; vesicle fusion

DOI:  https://doi.org/10.7554/eLife.102857
PLoS Pathog. 2025 May 30. 21(5): e1012879

Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation.

Geneva N Kwaku, Kirstine Nolling Jensen, Patricia Simaku, Daniel J Floyd, Joseph W Saelens, Christopher M Reardon, Rebecca A Ward, Kyle J Basham, Olivia W Hepworth, Tammy D Vyas, Daniel Zamith-Miranda, Joshua D Nosanchuk, Jatin M Vyas, Hannah Brown Harding.

Microbial pathogens generate extracellular vesicles (EVs) for intercellular communication and quorum sensing. Microbial EVs also induce inflammatory pathways within host innate immune cells. We previously demonstrated that EVs secreted by Candida albicans trigger type I interferon signaling in host cells specifically via the cGAS-STING innate immune signaling pathway. Here, we show that despite sharing similar properties of morphology and internal DNA content, the interactions between EVs and the innate immune system differ according to the parental fungal species. EVs secreted by C. albicans, Saccharomyces cerevisiae, Cryptococcus neoformans, and Aspergillus fumigatus are differentially endocytosed by murine macrophages triggering varied cytokine responses, innate immune signaling, and subsequent immune cell recruitment. Notably, polysaccharide and hydrophobic protein structures on the outer layers of C. neoformans and A. fumigatus EVs inhibit efficient internalization by macrophages and dampen innate immune activation. Our data uncover the functional consequences of the internalization of diverse fungal EVs by immune cells and reveal novel insights into the early innate immune response to distinct clinically significant fungal pathogens.

DOI: https://doi.org/10.1371/journal.ppat.1012879