Psoriasis Pathogenesis: Current Insights into Key Mechanisms

Psoriasis is a chronic inflammatory skin disease marked by abnormal immune activation and excessive keratinocyte proliferation. It affects millions worldwide, causing red, scaly plaques that significantly impact quality of life. While its exact cause remains complex, research has provided deeper insights into the mechanisms driving its development.

Recent findings highlight the interplay between genetic susceptibility, immune system dysregulation, and environmental triggers in psoriasis. Understanding these factors is essential for developing more effective treatments and improving patient outcomes.

Genetic Predisposition

Psoriasis has a strong hereditary component, with family history being a major risk factor. Genome-wide association studies (GWAS) have identified over 60 susceptibility loci, with the PSORS1 locus on chromosome 6p21.3 being the most well-established. This region contains the HLA-C06:02 allele, strongly linked to early-onset and severe psoriasis. Individuals carrying this allele face a significantly higher likelihood of developing the disease.

Beyond HLA-C06:02, other genetic variants contribute to susceptibility, particularly those affecting epidermal barrier function and inflammatory pathways. Mutations in LCE3B and LCE3C, which encode proteins essential for skin integrity, have been linked to increased risk. Deficiencies in these proteins may weaken the skin barrier, facilitating lesion development. Additionally, polymorphisms in CARD14, a gene involved in keratinocyte signaling, have been implicated in familial psoriasis, underscoring its genetic complexity.

Gene-environment interactions also influence psoriasis. Twin studies show concordance rates of about 70% in monozygotic twins, indicating that while genetics play a dominant role, external factors contribute to disease manifestation. Epigenetic modifications, such as DNA methylation and histone acetylation, have been observed in psoriatic skin, suggesting environmental exposures can modulate gene expression and impact disease progression.

Immune Cell Roles

Psoriasis is driven by immune cell interactions that sustain chronic inflammation and epidermal changes. T cells and dendritic cells play central roles, while keratinocytes actively amplify inflammatory signals.

T Cells

CD4+ and CD8+ T cells are key mediators of psoriasis. In psoriatic lesions, CD8+ T cells infiltrate the epidermis, while CD4+ T cells accumulate in the dermis. Activated by antigen-presenting cells, they secrete pro-inflammatory cytokines like interleukin-17 (IL-17) and interferon-gamma (IFN-γ), driving keratinocyte hyperproliferation. Th17 cells, which produce IL-17A and IL-17F, are particularly significant. Blocking IL-17 signaling with monoclonal antibodies such as secukinumab and ixekizumab leads to substantial clinical improvement, reinforcing Th17’s role in disease progression. Regulatory T cells (Tregs), which normally suppress immune responses, exhibit functional impairments in psoriasis, exacerbating immune dysregulation.

Dendritic Cells

Dendritic cells (DCs) initiate and sustain psoriatic inflammation. Plasmacytoid dendritic cells (pDCs) are among the first immune cells activated in lesional skin, releasing type I interferons (IFN-α and IFN-β) in response to endogenous nucleic acids. This promotes the maturation of myeloid dendritic cells (mDCs), which produce IL-23, a key driver of Th17 differentiation. Elevated IL-23 levels correlate with disease severity, and therapies targeting IL-23, such as guselkumab and risankizumab, have shown significant efficacy. DCs also interact with keratinocytes, releasing tumor necrosis factor-alpha (TNF-α) and IL-20, further amplifying inflammation. Their persistence in psoriatic lesions underscores their role in chronic disease progression.

Keratinocyte Interactions

Keratinocytes, the predominant epidermal cells, actively contribute to psoriasis. In response to cytokines like IL-17, IL-22, and TNF-α, they proliferate excessively and differentiate abnormally, forming thick, scaly plaques. They also produce antimicrobial peptides like LL-37, which can complex with self-DNA and activate pDCs, perpetuating immune responses. Additionally, keratinocytes release chemokines such as CCL20, recruiting more Th17 cells and reinforcing inflammation. Targeting keratinocyte signaling, such as the Janus kinase (JAK)-STAT pathway, has shown promise in reducing disease severity.

Cytokine Signaling

Psoriasis is sustained by a network of cytokines that drive chronic inflammation. The IL-23/IL-17 axis is central, with IL-23 stabilizing and expanding IL-17-producing cells, which in turn promote keratinocyte hyperproliferation. Biologics targeting this pathway, such as guselkumab and secukinumab, have demonstrated significant efficacy.

TNF-α amplifies inflammation by inducing additional cytokine release and attracting immune cells to psoriatic lesions. TNF-α inhibitors like adalimumab and etanercept have shown clinical benefits, though some patients exhibit incomplete responses, suggesting redundant cytokine pathways sustain disease activity. IL-22 further exacerbates epidermal abnormalities by promoting proliferation while impairing differentiation, contributing to the formation of thick plaques.

Other cytokines, including interferons and IL-36, also play roles in psoriasis. Type I interferons, particularly IFN-α, are implicated in early disease initiation, while IL-36, significantly upregulated in psoriatic lesions, fuels inflammation and disrupts skin homeostasis. Mutations in IL36RN, encoding an IL-36 receptor antagonist, are linked to generalized pustular psoriasis, highlighting IL-36’s pathological role.

Environmental Factors

Various environmental triggers influence psoriasis onset and severity. Physical trauma, known as the Köbner response, can induce lesions in predisposed individuals. Even minor injuries like cuts or friction from clothing can trigger plaques. This effect is commonly observed in patients undergoing tattooing or surgery.

Lifestyle factors such as smoking and alcohol consumption are associated with increased disease severity. Tobacco smoke contains oxidative compounds that disrupt skin homeostasis, while chronic alcohol use has been linked to higher prevalence and reduced treatment efficacy. A meta-analysis in JAMA Dermatology found heavy alcohol use increased psoriasis risk by 60%. Certain medications, including beta-blockers, lithium, and antimalarial drugs, can also worsen psoriasis, likely due to their effects on skin cell turnover and inflammation.

Microbiome Interplay

The skin microbiome plays a role in maintaining epidermal homeostasis and regulating inflammation. In psoriasis, microbial composition shifts toward pro-inflammatory species while reducing beneficial commensals. 16S rRNA sequencing studies reveal decreased Cutibacterium acnes and Staphylococcus epidermidis, which protect the skin barrier, alongside increased Streptococcus and Corynebacterium, which may contribute to immune activation.

Fungal and viral elements also contribute. Malassezia, a yeast commonly found on skin, has been implicated in scalp psoriasis, where its overgrowth is frequently observed. Certain Malassezia species produce bioactive metabolites that trigger immune responses, amplifying inflammation. Additionally, emerging evidence links psoriasis to human papillomavirus (HPV) and Epstein-Barr virus (EBV), which may act as environmental triggers in genetically susceptible individuals. These findings suggest microbiome-targeted therapies, such as probiotics, may help manage disease severity.

Epidermal Remodeling

Psoriatic lesions exhibit profound epidermal remodeling due to excessive keratinocyte proliferation and disrupted differentiation. Unlike normal skin, where keratinocytes mature over approximately 28 days, psoriatic epidermis undergoes accelerated turnover in just 3 to 5 days. This results in immature keratinocytes accumulating, forming thick plaques and silvery scales. Dysregulated expression of keratin-6, keratin-16, and keratin-17 further contributes to structural abnormalities.

Defects in the cornified envelope, essential for skin barrier function, also play a role. Key proteins like filaggrin, loricrin, and involucrin are often dysregulated in psoriatic plaques, leading to increased transepidermal water loss and heightened sensitivity to irritants. This impaired barrier function allows microbial products and inflammatory mediators to penetrate, perpetuating chronic inflammation. Advances in topical therapies, such as vitamin D analogs and retinoids, aim to restore normal keratinocyte differentiation, offering targeted approaches to improving lesion resolution and long-term management.