# Understanding the Intricate Pathophysiology of Psoriasis and Related Skin Disorders
## 4 Sporiasis and Associated Dermatologic Disorders
The broad range of cytokines and chemokines, along with adipokines, leptin, and fatty acids, leads to the exacerbation of psoriasis and AD and a significant reduction in treatment effectiveness. The stress experienced during adipose tissue expansion in obesity may stretch the epidermis, resulting in a compromised epidermal barrier function and triggering the innate immune response, which can initiate autoimmune activation. Proinflammatory molecules, including free fatty acids, adipokines, and cytokines released from expanding adipose tissue, can activate innate immune cells such as neutrophils, macrophages, and dendritic cells. This activation leads to the stimulation of Th1, Th17, and/or Th22 cells, ultimately resulting in epidermal hyperplasia. Adiponectin, an anti-inflammatory adipokine, normally inhibits the activation of myeloid and lymphocyte cells. However, in obese individuals, the expression of ADIPOQ is diminished in hypertrophied adipocytes, which may play a role in the development of psoriasis and/or atopic dermatitis. A compromised skin barrier can allow allergens and pathogens to enter, fostering a Th2 immune response that drives acute allergic inflammation and contributes to the pathogenesis of atopic dermatitis [62]. Psoriasis is classified as a T cell-mediated disorder, as T cell-derived cytokines like IL-17A and IL-22 are responsible for the hyperproliferation and abnormal differentiation of keratinocytes, leading to the formation of psoriatic plaques. However, the recognition of DAMPs or PAMPs by pattern recognition receptors (PRRs) in keratinocytes or plasmacytoid dendritic cells (pDCs) is believed to trigger the initial events in psoriasis. These events set off innate immune responses that drive the later development of adaptive immunity and autoimmunity. In response to DAMP or PAMP stimulation, keratinocytes can produce a range of proinflammatory cytokines, including IFN-\(\beta\), IL-19, IL-36, TNF, IL-6, IL-8, IL-25, and CXCL10, which help establish the inflammatory T cell phenotype characteristic of psoriasis [63]. PRR-mediated activation of innate immune responses in keratinocytes contributes to the onset of psoriasis following skin injury. When the skin is damaged, cells release DAMPs such as dsRNA, ssRNA, and DNA. Notably, the antimicrobial peptide LL37, which is upregulated during wounds, facilitates the recognition of dsRNA in keratinocytes via the TLR3 and mitochondrial MAVS (mitochondrial antiviral signaling protein) pathways, leading to IFN-\(\beta\) production by keratinocytes or pDCs. It was demonstrated that LL37 enables pDCs to recognize ssRNA or DNA through TLR7 or TLR9, resulting in significant IFN-\(\alpha\) production. Furthermore, self-ssRNA-LL37 complexes activate conventional dendritic cells via TLR8, promoting the release of TNF-\(\alpha\) and IL-6 and aiding in cDC maturation. The roles of TLR2 and TLR4 in psoriasis remain ambiguous. TLR2 and TLR4 expressions are heightened in peripheral blood mononuclear cells and keratinocytes of psoriasis patients. Additionally, polymorphisms within TLR4 have been linked to chronic plaque psoriasis and psoriatic arthritis. Recent studies indicate that neutrophil infiltration into the epidermis triggers inflammatory responses by activating the epidermal TLR4-IL36 Rcrosstalk in an imiquimod-induced psoriasis-like mouse model. Moreover, heat shock proteins (HSPs) such as HSP27, HSP60, HSP70, and HSP90 are overexpressed in psoriasis keratinocytes, acting as autoantigens that activate antigen-presenting cells via TLR4, promoting their maturation and the secretion of TNF-\(\alpha\) and IL-12 [63; 64]. The skin barrier-inflammatory pathway plays a role in driving the transition from psoriasis to atopic dermatitis. The skin barrier is formed by physical components such as keratinocytes, keratin, cornified cell envelope (CE), intercellular lipids, and skin connective structures, as well as chemical components such as antimicrobial peptides and natural moisturizing factors (NMFs).