Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis
Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-ass...
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MDPI AG
2025-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/14/12/930 |
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| author | Jhan S. Saavedra-Torres María Virginia Pinzón-Fernández Martin Ocampo-Posada H. A. Nati-Castillo Laura Alejandra Jiménez Hincapie Eder J. Cadrazo-Gil Marlon Arias-Intriago Marlon Rojas-Cadena Andrea Tello-De-la-Torre Walter Osejos Juan S. Izquierdo-Condoy |
| author_facet | Jhan S. Saavedra-Torres María Virginia Pinzón-Fernández Martin Ocampo-Posada H. A. Nati-Castillo Laura Alejandra Jiménez Hincapie Eder J. Cadrazo-Gil Marlon Arias-Intriago Marlon Rojas-Cadena Andrea Tello-De-la-Torre Walter Osejos Juan S. Izquierdo-Condoy |
| author_sort | Jhan S. Saavedra-Torres |
| collection | DOAJ |
| description | Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D–mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival. |
| format | Article |
| id | doaj-art-607bc3cfded04705b06c6116b80c028f |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-607bc3cfded04705b06c6116b80c028f2025-08-20T03:27:22ZengMDPI AGCells2073-44092025-06-01141293010.3390/cells14120930Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of SepsisJhan S. Saavedra-Torres0María Virginia Pinzón-Fernández1Martin Ocampo-Posada2H. A. Nati-Castillo3Laura Alejandra Jiménez Hincapie4Eder J. Cadrazo-Gil5Marlon Arias-Intriago6Marlon Rojas-Cadena7Andrea Tello-De-la-Torre8Walter Osejos9Juan S. Izquierdo-Condoy10Grupo de Investigación en Salud (GIS), Universidad del Cauca, Popayan 190002, ColombiaGrupo de Investigación en Salud (GIS), Universidad del Cauca, Popayan 190002, ColombiaGrupo de Investigación en Ciencias Básicas y Clínicas de la Salud, Universidad Javeriana, Cali 760031, ColombiaInterinstitutional Group of Internal Medicine (GIMI I), Universidad Libre, Cali 760031, ColombiaFacultad de Medicina, Fundación Universitaria Autónoma de las Américas, Pereira 660003, ColombiaFacultad de Medicina, Universidad del Norte, Barranquilla 081007, ColombiaOne Health Research Group, Universidad de las Américas, Quito 170124, EcuadorOne Health Research Group, Universidad de las Américas, Quito 170124, EcuadorOne Health Research Group, Universidad de las Américas, Quito 170124, EcuadorDepartamento de Medicina Interna, Clínica Guayaquil, Guayaquil 090313, EcuadorOne Health Research Group, Universidad de las Américas, Quito 170124, EcuadorSepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D–mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival.https://www.mdpi.com/2073-4409/14/12/930sepsisinflammasomepyroptosiscytokinescoagulationimmunomodulation |
| spellingShingle | Jhan S. Saavedra-Torres María Virginia Pinzón-Fernández Martin Ocampo-Posada H. A. Nati-Castillo Laura Alejandra Jiménez Hincapie Eder J. Cadrazo-Gil Marlon Arias-Intriago Marlon Rojas-Cadena Andrea Tello-De-la-Torre Walter Osejos Juan S. Izquierdo-Condoy Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis Cells sepsis inflammasome pyroptosis cytokines coagulation immunomodulation |
| title | Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis |
| title_full | Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis |
| title_fullStr | Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis |
| title_full_unstemmed | Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis |
| title_short | Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis |
| title_sort | inflammasomes and signaling pathways key mechanisms in the pathophysiology of sepsis |
| topic | sepsis inflammasome pyroptosis cytokines coagulation immunomodulation |
| url | https://www.mdpi.com/2073-4409/14/12/930 |
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