[Academic Presentation] Recent Advances in Immunological Research on the Association Between Common Adipokines and Psoriasis

Leptin is a key regulator of appetite and energy expenditure, primarily produced by adipocytes in white adipose tissue; however, studies have also demonstrated that it can be synthesized in non‑adipose tissues, such as the gastric mucosa and placental trophoblasts. Leptin is known to play an important role in chronic inflammatory states, including obesity. In obese individuals and during chronic inflammation, leptin levels are elevated yet fail to exert their normal functions—such as suppressing appetite and reducing food intake—leading some to propose that these patients exhibit reduced or absent sensitivity to leptin, resulting in leptin resistance. The underlying mechanisms remain incompletely understood; emerging evidence suggests that leptin resistance may be associated with mutations in the leptin receptor, OB‑R. Additionally, proteins such as IL‑1Ra and suppressor of cytokine signaling 3 (SOCS3) may exert negative feedback inhibition on leptin signaling, thereby promoting the development of leptin resistance. Hamminga et al. hypothesize that elevated leptin levels in obese patients might contribute to the pathogenesis of psoriasis by triggering the release of pro‑inflammatory cytokines. Weight loss markedly reduces leptin levels, improves insulin sensitivity, and lowers the risk of metabolic syndrome and cardiovascular disease. In patients with severe psoriasis, both leptin and its receptor are expressed at significantly higher levels than in healthy controls. Moreover, the increased circulating leptin observed in psoriatic patients arises not only from adipose tissue but also from inflammatory processes.

Leptin receptors exist in multiple isoforms, among which the long‑form receptor isoform OB‑Rb possesses signaling capabilities and serves as the primary receptor mediating leptin’s biological functions. Leptin receptors belong to the IL‑6 receptor family; they lack intrinsic enzymatic activity and primarily transduce signals by activating Janus kinase 2 (JAK2). Upon binding to JAK2, the receptor activates suppressor of cytokine signaling 3 (SOCS3), which is one of the negative feedback regulators of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Soluble leptin receptor is the major binding protein for leptin in human blood, generated through proteolytic shedding of the extracellular domain of cell‑surface leptin receptors, and it modulates leptin bioavailability. Plasma concentrations of soluble leptin receptor vary across different metabolic disorders, with corresponding differences in leptin sensitivity. Obesity, insulin resistance, type 2 diabetes, and other conditions have been shown to be negatively correlated with soluble leptin receptor levels; however, the status of soluble leptin receptor levels in patients with psoriasis remains unclear.

Research has shown that leptin promotes the proliferation, differentiation, and migration of keratinocytes, as well as the secretion of numerous pro-inflammatory cytokines, and it also stimulates angiogenesis. Co-culture experiments with fibroblasts revealed that pro-inflammatory factors such as interleukin‑6 (IL‑6), chemokine CXCL‑1, monocyte chemoattractant protein‑1 (MCP‑1), interleukin‑8 (IL‑8), angiopoietin‑1, and stromal cell‑derived factor‑1 (SDF‑1) are significantly upregulated; moreover, leptin induces fibroblasts in psoriatic lesions to secrete increased amounts of the cell adhesion molecule intercellular adhesion molecule‑1 (ICAM‑1). In vitro studies have confirmed that leptin enhances the differentiation of CD4+ T cells into Th17 cells, an effect mediated by the leptin receptor, and it further promotes IL‑17 secretion by T cells. In monocytes, leptin elevates the expression of multiple activation markers, augments phagocytic activity, and upregulates cytokine production. In endothelial cells, leptin increases the expression of adhesion molecules and induces oxidative stress. Leptin thus plays a dual role in inflammation: on the one hand, it activates monocytes and macrophages and stimulates the secretion of pro-inflammatory cytokines such as TNF‑α, IL‑6, and IL‑9; on the other hand, it can direct T cell differentiation toward the Th1 phenotype. These findings indicate that leptin not only drives the secretion of inflammatory cytokines by various skin cell types but also modulates the surface‑expressed molecules of infiltrating immune cells, enabling them to adapt to the local microenvironment, thereby exerting a pro‑inflammatory effect in the pathogenesis of psoriasis.

Adiponectin is primarily secreted by white adipose tissue. Previously regarded as a metabolic intermediate in insulin resistance, it is now recognized as a mediator of immune responses. Adiponectin monomers can oligomerize into trimers via their collagen-like domains; however, both trimers and higher-order oligomers coexist in peripheral blood, and these distinct forms may exert different effects on insulin sensitivity. Activated immune cells release neutrophil elastase, which cleaves adiponectin; the resulting peptide fragments may exhibit disparate biological activities. Adiponectin exerts differential regulatory effects across various disease states. In metabolic disorders such as type 2 diabetes and metabolic syndrome, adiponectin levels are inversely correlated with those of TNF‑α and IL‑6, suggesting that adiponectin suppresses inflammation during conditions of positive energy balance. Studies indicate that adiponectin may mediate its anti‑inflammatory actions by inhibiting NF‑κB activity. Conversely, in autoimmune and chronic inflammatory diseases—including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus—adiponectin can upregulate the expression of pro‑inflammatory cytokines such as IL‑6 and MCP‑1, thereby promoting inflammatory processes. These findings underscore adiponectin’s bidirectional regulatory role. By binding to its receptors, AdipoR1 and AdipoR2, adiponectin activates multiple signaling pathways, including AMPK, p38‑MAPK, c‑Jun N‑terminal kinase (JNK), peroxisome proliferator‑activated receptor‑α (PPAR‑α), and nuclear factor‑κB (NF‑κB). Upon engagement with AdipoR1/AdipoR2, adiponectin also stimulates keratinocyte proliferation and migration through the extracellular signal‑regulated kinase (ERK) pathway. Jung et al. demonstrated that adiponectin, via the phospholipase C‑γ (PLCγ)/JNK/NF‑κB signaling cascade, enhances MHC class II molecule expression in dendritic cells, facilitating their maturation, activation, and secretion of potent pro‑inflammatory cytokines. Moreover, adiponectin treatment of dendritic cells promotes Th1 and Th17 cell responses both in vitro and in vivo. In a classic imiquimod‑induced psoriasis‑like murine model, adiponectin directly modulates dermal γδ T cells, suppressing IL‑17 synthesis through AdipoR1. Concurrently, reduced adiponectin levels have been observed in the skin tissues of psoriasis patients, particularly within subcutaneous adipose tissue, providing evidence for adiponectin’s involvement in the pathogenesis of psoriasis. Adiponectin induces monocytes and macrophages to release anti‑inflammatory factors, including IL‑10 and the IL‑1 receptor antagonist, thereby attenuating IL‑6 levels. It also inhibits TNF‑α secretion and its bioactivity, while TNF‑α, in turn, suppresses adiponectin production. In endothelial cells, contrary to the effects of TNF‑α, adiponectin downregulates the expression of the adhesion molecules ICAM‑1 and vascular cell adhesion molecule‑1 (VCAM‑1). Taken together, researchers conclude that adiponectin exerts beneficial effects.