Inflammatory Mechanisms in Psoriatic Skin Diseases

Psoriasis is driven by a complex interplay between innate and adaptive immunity, characterised by dysregulated keratinocyte proliferation, barrier disruption and a self‐sustaining inflammatory milieu. Central to this process is the IL-23–Th17 axis, which amplifies production of interleukin-17 and interleukin-22, promoting keratinocyte activation and neutrophil recruitment. Neutrophils release neutrophil extracellular traps (NETs) in a process known as NETosis, enriching the local environment with DNA, RNA and antimicrobial peptides such as LL37. These NET components engage Toll-like receptors on dendritic cells and keratinocytes, fuelling cytokine cascades and establishing a feedback loop that perpetuates epidermal inflammation. Parallel activation of inflammasomes within keratinocytes and myeloid cells generates mature IL-1β and IL-18, further intensifying Th17 responses and systemic inflammation. Crosstalk among keratinocytes, neutrophils, dendritic cells and T cells underlies the formation of psoriatic plaques, while systemic spill-over of inflammatory mediators links skin disease to comorbidities such as cardiovascular dysfunction. Emerging evidence highlights the potential to disrupt key nodal points—NET formation, inflammasome assembly and receptor‐mediated amplification—to achieve sustained remission.

Research from Nature Portfolio

Recent studies have uncovered a self-propagating loop driven by NET-associated RNA in complex with LL37, which triggers Toll-like receptor 8–mediated cytokine release and secondary NETosis. This vicious cycle amplifies local inflammation and may explain chronic plaque persistence. Foundational work has also demonstrated that NET density in both blood and lesional skin correlates with disease severity and induces human β-defensin-2 production by keratinocytes, offering a mechanistic link between neutrophil activity and enhanced antimicrobial peptide expression in psoriatic plaques.

Inflammatory Mechanisms in Psoriatic Skin Diseases publication trend

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

Technical terms

Neutrophil extracellular trap (NET): A web-like structure of DNA, histones and antimicrobial proteins released by neutrophils during NETosis to trap pathogens.

NETosis: A form of neutrophil cell death resulting in NET release and promotion of inflammation.

Inflammasome: A multiprotein intracellular complex that activates caspase enzymes leading to maturation of proinflammatory cytokines IL-1β and IL-18.

IL-23–Th17 axis: A cytokine pathway whereby interleukin-23 drives differentiation of Th17 cells, crucial for psoriatic inflammation.

Keratinocyte: The primary cell type in the epidermis that plays a central role in barrier function and cytokine production in psoriasis.

References

1. NETosis of psoriasis: a critical step in amplifying the inflammatory response. Frontiers in Immunology (2024).
2. Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes. Scientific Reports (2016).
3. Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis. Nature Communications (2020).
4. Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation. Journal of Investigative Dermatology (2020).
5. Immunomodulatory aged neutrophils are augmented in blood and skin of psoriasis patients. Journal of Allergy and Clinical Immunology (2021).