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Peer-reviewedCC BYFrontiers in immunology

Human macrophages activate a coordinated program linking inflammation and cell death in response to intracellular Poly(I:C)

  • Luigi Fiore1
  • Lara Di Leonardo1
  • Marco Buscetta1
  • Maria Concetta Volpe1
  • Marta Cristaldi1
  • Maria Rita Giuffrè1
  • Chiara Finocchio1
  • Gioacchin Iannolo2
  • Germana Lentini3
  • Giuseppe Teti4
  • Alice Conigliaro5
  • Harald Husebye6
2 more authors
  • Concetta Beninati3
  • Chiara Cipollina1
6 affiliations
  1. 1Ri.MED Foundation , ,
  2. 2IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione) , ,
  3. 3Dipartimento di Patologia Umana, Università Degli Studi di Messina , ,
  4. 4Scylla Biotech Srl , ,
  5. 5Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università Degli Studi di Palermo , ,
  6. 6Centre of Molecular Inflammation Research, Department of Clinical Molecular Medicine, Norwegian University of Science and Technology , ,
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Abstract

Background: Macrophages sense viral double-stranded RNA (dsRNA) via the innate immune receptors TLR3 and MDA5 whose activation drives a robust inflammatory program, often coupled to cell death. TLR3/TRIF-dependent apoptosis has been described in response to dsRNA. Growing evidence suggests that dsRNA may trigger multiple forms of cell death with mechanisms yet to be elucidated. In addition to TLR/TRIF axis, the necroptosis regulator RIPK3 has been implicated in both inflammatory response and cell death during viral infections in several cell types. However, its role in regulating these two events in human macrophages remains unclear.

Methods: Here, we investigated in human monocyte-derived macrophages (hMDMs) the mechanisms of dsRNA induced cell death and its temporal and molecular linkage to inflammatory signaling, with a focus on the interplay between RIPK3 and the TLR3/TRIF pathways.

Results: We found that intracellular Poly(I:C), a synthetic analogue of dsRNA, induced cell death with apoptotic and necroptotic features. TRIF-mediated signaling cascade and RIPK3 jointly contributed to caspase-8 activation leading to apoptosis. RIPK3 also promoted necroptosis by inducing MLKL phosphorylation. Downstream of caspases, Poly(I:C) induced cleavage of Gasdermin E (GSDME), which remained intracellular and localized in mitochondria contributing to the amplification of caspase-3 activation. RIPK3-dependent signaling drove the release of IFN-β and TNF-α and promoted the upregulation of the sensors TLR3 and MDA5, thereby amplifying the inflammatory axis. The inflammatory response preceded cell death, with RIPK3 being the key regulator of the early signaling and TLR3/TRIF becoming involved at later timepoints.

Conclusions: Collectively, these findings identify RIPK3 as key mediator coordinating dsRNA-induced inflammatory signaling and regulated cell death in human macrophages.

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Cite

BibTeXRIS
BibTeX
@article{fiore2026human,
  title = {{Human macrophages activate a coordinated program linking inflammation and cell death in response to intracellular Poly(I:C)}},
  author = {Luigi Fiore and Lara Di Leonardo and Marco Buscetta and Maria Concetta Volpe and Marta Cristaldi and Maria Rita Giuffrè and Chiara Finocchio and Gioacchin Iannolo and Germana Lentini and Giuseppe Teti and Alice Conigliaro and Harald Husebye and Concetta Beninati and Chiara Cipollina},
  journal = {Frontiers in immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1827486},
  url = {https://europepmc.org/article/PMC/PMC13672200},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human macrophages activate a coordinated program linking inflammation and cell death in response to intracellular Poly(I:C)
AU  - Luigi Fiore
AU  - Lara Di Leonardo
AU  - Marco Buscetta
AU  - Maria Concetta Volpe
AU  - Marta Cristaldi
AU  - Maria Rita Giuffrè
AU  - Chiara Finocchio
AU  - Gioacchin Iannolo
AU  - Germana Lentini
AU  - Giuseppe Teti
AU  - Alice Conigliaro
AU  - Harald Husebye
AU  - Concetta Beninati
AU  - Chiara Cipollina
PY  - 2026
DA  - 2026/10/02
JO  - Frontiers in immunology
DO  - 10.3389/fimmu.2026.1827486
UR  - https://europepmc.org/article/PMC/PMC13672200
AB  - Background: Macrophages sense viral double-stranded RNA (dsRNA) via the innate immune receptors TLR3 and MDA5 whose activation drives a robust inflammatory program, often coupled to cell death. TLR3/TRIF-dependent apoptosis has been described in response to dsRNA. Growing evidence suggests that dsRNA may trigger multiple forms of cell death with mechanisms yet to be elucidated. In addition to TLR/TRIF axis, the necroptosis regulator RIPK3 has been implicated in both inflammatory response and cell death during viral infections in several cell types. However, its role in regulating these two events in human macrophages remains unclear.  Methods: Here, we investigated in human monocyte-derived macrophages (hMDMs) the mechanisms of dsRNA induced cell death and its temporal and molecular linkage to inflammatory signaling, with a focus on the interplay between RIPK3 and the TLR3/TRIF pathways.  Results: We found that intracellular Poly(I:C), a synthetic analogue of dsRNA, induced cell death with apoptotic and necroptotic features. TRIF-mediated signaling cascade and RIPK3 jointly contributed to caspase-8 activation leading to apoptosis. RIPK3 also promoted necroptosis by inducing MLKL phosphorylation. Downstream of caspases, Poly(I:C) induced cleavage of Gasdermin E (GSDME), which remained intracellular and localized in mitochondria contributing to the amplification of caspase-3 activation. RIPK3-dependent signaling drove the release of IFN-β and TNF-α and promoted the upregulation of the sensors TLR3 and MDA5, thereby amplifying the inflammatory axis. The inflammatory response preceded cell death, with RIPK3 being the key regulator of the early signaling and TLR3/TRIF becoming involved at later timepoints.  Conclusions: Collectively, these findings identify RIPK3 as key mediator coordinating dsRNA-induced inflammatory signaling and regulated cell death in human macrophages.
SN  - 1664-3224
ER  -