Inflammasome Activation and Inflammatory Responses

Inflammasomes are cytosolic multiprotein platforms that sense pathogenic or stress signals and initiate innate immune defences. Upon recognition of danger-associated or pathogen-associated molecular patterns, sensor proteins such as NLRP3 undergo conformational change and recruit adaptor proteins and inflammatory caspases to assemble a signalling hub. Activation of caspase-1 leads to the maturation and secretion of interleukin-1β and interleukin-18, and to the proteolytic cleavage of gasdermin D, whose pore-forming N-terminal fragment triggers pyroptotic cell death. Pyroptosis releases pro-inflammatory mediators, including damage-associated molecular patterns (DAMPs), which amplify local and systemic responses. While controlled inflammasome activation is vital for host defence against infection and tissue injury, dysregulated or chronic activation underlies autoinflammatory disorders, metabolic disease, neurodegeneration and cancer. Consequently, detailed understanding of the molecular mechanisms governing inflammasome assembly, activation and resolution has become a central goal in immunology, with direct implications for therapeutic modulation in a range of human diseases.

Research from Nature Portfolio

Recent studies have identified novel regulators of cell death and inflammation. In one investigation, monoclonal antibodies targeting the cell-surface protein NINJ1 were shown to inhibit plasma membrane rupture during pyroptosis and apoptosis. By preventing NINJ1 oligomerisation, these antibodies reduced release of DAMPs and pro-inflammatory cytokines, attenuating liver injury and neutrophil infiltration in murine models of hepatitis and ischaemia–reperfusion. In a separate advance, an amphiphilic photocatalyst localised to intracellular membranes was used to induce oxidative damage selectively to membrane proteins. This oxidative stress provoked non-canonical activation of inflammasome caspases and gasdermin D cleavage under hypoxic conditions, revealing a previously unrecognised trigger for lytic cell death and inflammatory signalling.

Inflammasome Activation and Inflammatory Responses publication trend

The graph below shows the total number of articles in inflammasome activation and inflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Inflammasome: A multiprotein complex that detects cellular stress or infection and activates inflammatory caspases.

Pyroptosis: A lytic form of programmed cell death driven by inflammatory caspases and gasdermin-mediated membrane pore formation.

Caspase-1: An inflammatory protease that processes interleukin-1β and interleukin-18 and initiates pyroptosis.

Gasdermin D: A pore-forming protein cleaved by inflammatory caspases to execute pyroptotic cell death.

Damage-associated molecular patterns (DAMPs): Endogenous molecules released by dying cells that amplify inflammatory responses.

NLRP3: A sensor protein of the nucleotide-binding domain and leucine-rich repeat receptor family that nucleates inflammasome assembly.

References

1. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. Nature (2023).
2. Oxidative photocatalysis on membranes triggers non-canonical pyroptosis. Nature Communications (2024).
3. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discovery (2020).
4. Toward targeting inflammasomes: insights into their regulation and activation. Cell Research (2020).
5. NLRP3 Inflammasome and Inflammatory Diseases. Oxidative Medicine and Cellular Longevity (2020).