Inflammatory Mechanisms in Autoinflammatory Diseases

Autoinflammatory diseases arise from aberrant activation of the innate immune system in the absence of detectable pathogens or high-titre autoantibodies. Central to these disorders is dysregulation of molecular platforms such as inflammasomes, which drive caspase-1-dependent maturation of interleukin-1β (IL-1β) and IL-18. Excessive cytokine release orchestrates neutrophil and monocyte recruitment, leading to tissue damage through proteases, reactive oxygen species and neutrophil extracellular traps. Genetic mutations affecting regulatory proteins—such as components of ubiquitin ligase complexes, adaptor molecules or phosphatases—can lower the threshold for inflammasome assembly and amplify NF-κB-mediated transcription. The resulting sterile inflammation manifests in diverse clinical syndromes, from periodic fevers to chronic osteomyelitis, underscoring the critical balance between homeostatic control and hyperinflammatory responses in innate immunity.

Research from Nature Portfolio

Studies in a mouse model lacking SHARPIN demonstrate a specific role for IL-1β signalling in driving skin and systemic inflammation. Loss of this component of the linear ubiquitin chain assembly complex leads to spontaneous dermatitis marked by neutrophil infiltration and tissue destruction. Experimental disruption of IL-1β, but not IL-1α, signalling in these animals abrogates disease development, highlighting the therapeutic potential of selective IL-1β blockade. These findings elucidate how dysregulated ubiquitin-mediated control of NF-κB and inflammasome activation converges on IL-1β maturation to precipitate autoinflammation.

Inflammatory Mechanisms in Autoinflammatory Diseases publication trend

The graph below shows the total number of articles in inflammatory mechanisms in autoinflammatory diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Inflammasome: A multi-protein platform that activates caspase-1 to process pro-IL-1β into its active form.

IL-1β: A pro-inflammatory cytokine central to innate immune activation and autoinflammatory pathology.

PSTPIP2: An adaptor protein that binds signalling phosphatases to regulate neutrophil function and inflammatory homeostasis.

PEST-type phosphatase: A family of protein tyrosine phosphatases that modulate inflammatory signalling through interaction with adaptor proteins.

Neutrophil extracellular traps (NETs): Web-like DNA and protein structures released by neutrophils that can exacerbate inflammation.

References

1. Auto-inflammatory diseases. Pediatric Rheumatology (2014).
2. Distinct role of IL-1β in instigating disease in Sharpincpdm mice. Scientific Reports (2016).
3. Genetic background affects neutrophil activity and determines the severity of autoinflammatory osteomyelitis in mice. Journal of Leukocyte Biology (2024).
4. Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation. Frontiers in Immunology (2022).