Qingguo Ruan

Autoimmune diseases (ADs) are a group of inflammatory disorders triggered by aberrant immune responses against autoantigens and the breakdown of immune tolerance. Current therapeutic strategies, such as glucocorticoids and immunosuppressants, exert largely non-specific immunomodulation and are frequently associated with substantial adverse effects upon long-term administration. As such, these approaches are often insufficient to re-establish immune homeostasis. In recent years, regulatory T cell (Treg)-based therapeutics have undergone rapid advancement, with continuously updated therapeutic modalities broadening the application boundary of immune tolerance intervention. This review comprehensively outlines the progress of Treg-based therapeutics, spanning from fundamental biological research to translational applications in autoimmune diseases. We describe the developmental characteristics, suppressive machinery, and heterogeneity of Tregs, and highlight the preclinical and clinical advancements of diverse Treg therapeutic modalities, including polyclonal and antigen-specific Tregs, TCR-engineered Tregs, and CAR-Tregs. Furthermore, we emphasize current optimization strategies for enhancing Treg stability, antigen specificity, and in vivo fitness within inflammatory microenvironments. Additionally, we objectively address the major translational bottlenecks of Treg therapy and provide future perspectives to facilitate the clinical implementation of Treg-based immunotherapies for autoimmune diseases.

Psoriasis is a chronic inflammatory autoimmune skin disease significantly impairing the patients’ quality of life. Keratin (K)14 and K17 are abnormally expressed in psoriasis patients and considered to be potential autoantigens triggering this disease. However, the animal model for psoriasis induced with a specific antigen is yet to be established. Here we show that vaccinating BALB/c and C57BL/6J mice with purified murine recombinant K14 or K17 antigen induced psoriasis-like clinical symptoms in 40 ± 30% of animals, such as erythema and scaling, accompanied by hallmark histopathological changes including significant epidermal hyperplasia and inflammatory cell infiltration in the lesions. Furthermore, the immunized mice produced high levels of specific antibodies against K14/K17 in the blood, along with antigen-specific T-cell responses. These data indicate that immunization of mice with K14 and K17 antigens could cause psoriasis-like symptoms with immunopathological features of psoriasis, providing a novel experimental animal model for investigating the pathogenesis of psoriasis and development of effective therapies.

Psoriasis is a chronic, relapsing, immune-mediated inflammatory dermatosis characterized by aberrant keratinocyte hyperproliferation and prominent infiltration of inflammatory leukocytes. Among the NF-κB transcription factor family, c-Rel is the first member conclusively implicated as a psoriasis susceptibility gene, and its dysregulated expression positively correlates with clinical disease activity. Mechanistically, c-Rel orchestrates pathogenic inflammation by coordinating immune-cell differentiation programs and inflammatory cytokine production, while also contributing to keratinocyte proliferation and inflammatory responses in non-hematopoietic compartments. Emerging therapeutic approaches that modulate c-Rel, ranging from biologics and small-molecule inhibitors to nucleic-acid-based interventions, have shown encouraging efficacy in both clinical study and experimental psoriasis models. However, key translational hurdles remain, including suboptimal delivery, incomplete target-cell specificity, and long-term safety concerns. Deeper delineation of upstream activation cues and cell-type-restricted c-Rel regulatory circuits will be essential to enable precision targeting of c-Rel in psoriasis.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by erythematous plaques covered with silvery-white scales, often accompanied by systemic complications such as psoriatic arthritis and cardiovascular diseases. The disease and its systemic complications substantially impair quality of life, compromise socioeconomic status, and threaten patient safety. The occurrence and progression of this disease are related to the IL-23/IL-17 axis and involve the aberrant activation and interactions of multiple immune cells, along with genetic predispositions and environmental triggers. Although current therapeutic approaches, including topical agents, systemic medications, biologic agents targeting key cytokines, and Janus Kinase inhibitors, can control symptoms and delay disease progression, a complete cure has not been achieved. Furthermore, these strategies face challenges relating to the cost, safety, efficacy and precision of targeting. This review summarizes recent advances in mechanistic research, highlighting the interplay among microorganisms, innate and adaptive immunity in psoriasis. We also evaluate a range of emerging therapies, including biologics, small-molecule inhibitors, Chimeric antigen receptor T-cell cell therapy, RNA interference-based strategies, and alternative medicine. Specifically, we focus on their novel mechanisms, efficacy challenges, safety profiles, and targeting accuracy. Finally, we assess their potential in personalized treatment, aiming to achieve long-term remission, and propose the future prospects of precision medicine in psoriasis management.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by erythematous plaques covered with silvery-white scales, often accompanied by systemic complications such as psoriatic arthritis and cardiovascular diseases. The occurrence and progression of this disease are related to the IL-23/IL-17 axis and involve aberrant activation and interactions of multiple immune cells, including keratinocytes, dendritic cells, Th17 cells, and neutrophils, with genetic predispositions and environmental triggers. Currently, psoriasis remains incurable. Therapeutic strategies that primarily focus on immunosuppression, anti-inflammation, and palliative care can only control and delay disease progression. These strategies face challenges relating to cost, safety, efficacy and precision of targeting. Future research should prioritize individualized treatment, immune tolerance induction, and microbiome modulation to achieve long-term disease control and potential cure. This review is primarily focused on the progress and prospects of the pathogenesis and therapies for psoriasis, aiming to provide new insights for individualized treatment in the future.

Purpose: The purpose of this study was to determine the role of nuclear factor kappa B (NF-κB) c-Rel during acute corneal transplant rejection and whether targeting c-Rel can reduce corneal transplant rejection. Methods: Allogeneic corneal transplantation was performed in wild-type and c-Rel–deficient mice. Corneal graft survival rate, opacity, neovascularization, and edema were evaluated by slit-lamp microscopy. Adeno-associated virus 6 (AAV6) expressing c-Rel–specific small hairpin RNA (AAV6-shRel) and the small-molecule compound pentoxifylline (PTXF) were used to reduce c-Rel expression. Enzyme-linked immunosorbent assay was used to determine the expression of inflammatory cytokines. c-Rel expression was determined by quantitative RT-PCR and western blot. The effect of c-Rel inhibition on corneal transplant rejection was examined using a mouse model of acute allogeneic corneal transplantation. Tear production and corneal sensitivity were measured to determine the potential toxicity of AAV6-shRel and PTXF. Results: The expression of c-Rel and its inflammatory targets was increased in both mice and patients with corneal transplant rejection. Loss of c-Rel reduced corneal transplant rejection in mouse. Both AAV6-shRel and PTXF were able to downregulate the expression of c-Rel and its inflammatory targets in vitro. Treatment with AAV6-shRel or PTXF reduced corneal transplant rejection in mouse and downregulated the expression of inflammatory cytokines in peripheral blood mononuclear cells from patients with corneal transplant rejection. Treatment with AAV6-shRel or PTXF displayed no side effects on tear production or corneal sensitivity. Conclusions: Increased expression of c-Rel is a risk factor for acute corneal transplant rejection, and targeting c-Rel can efficiently reduce corneal transplant rejection.

The integrity of the corneal epithelium is essential for the maintenance of the physiological function of the cornea. Studies have found that inflammation greatly delays corneal wound healing. NF-κB c-Rel is preferentially expressed by immune cells and promotes the expression of inflammatory cytokines. In the current study, we sought to investigate whether c-Rel could be used as a potential therapeutic target for treating a corneal injury. Our studies reveal that expressions of c-Rel and its inflammatory targets are significantly increased in the cornea of mice with corneal injury. In addition, we find that c-Rel-deficient mice exhibit accelerated corneal wound healing and reduced expression of inflammatory cytokines. Further studies show that topical treatment on the corneal surface using nano-polymers or exosomes loaded with c-Rel-specific siRNA (siRel) can effectively accelerate regular and diabetic corneal wound healing. More importantly, we find that exosomes, as carriers of siRel, showed better efficacy than nano-polymers in treating corneal injury. We further demonstrate that exosomes secreted by mesenchymal stem cells can efficiently transfer siRNA into macrophages and dendritic cells but not T cells. Taken together, these results indicate that blocking c-Rel may represent an attracting strategy for the treatment of both regular and diabetic corneal injury.

Pancreatic β cell dysfunction contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we identify the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We find that miR-21βKO mice develop glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies reveal that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets results in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrate that delivery of miR-21 into the pancreas of type 2 diabetic db/db male mice is able to promote Glut2 expression and reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the regulation of pancreatic β cell function in type 2 diabetes.