Fang Zheng

Astrocytes are the primary source of high mobility group box-1 (HMGB1) which is intimately associated with aging and related disease in central nervous sys

Introduction: The Medical Immunology course is a basic and continuously updating medical course for medical students. As this course involves complex concepts, students are often frustrated by the amount of detailed material and find it hard to link the various knowledge points exactly and entirely. More effective and more engaging pedagogy beyond traditional didactic approaches is needed to drive students’ attention, understanding and memorizing more knowledge of medical immunology. Methods: In this article, we illustrate how Sandwich-based PBL approach is applied in a 4-class workshop to this course and how to assess its advantages by examination scores and questionnaire. Results: This Sandwich-based PBL approach could significantly improve students’ self-learning and critical thinking capabilities, communication skills and learning interests. Discussion: We need to make great efforts to maximize the advantages of the approach and to extend this approach to more departments or more basic courses.

Secreted high mobility group box protein 1 (HMGB1) regulates the adaptive immune response and acts as a biosensor for cells undergoing necrosis, stress, and inflammatory stimulation. However, its role in B cells remains enigmatic. Here, we demonstrate that HMGB1 is critical for peripheral B cell homeostasis and humoral immunity. Conditional deletion of Hmgb1 in B cells led to expanded marginal zone B cells, reduced B1a cells, and impaired antigen-specific antibody responses. Mechanistically, HMGB1 deficiency enhanced proximal and distal B cell receptor (BCR) signaling, probably via increased CD21 expression, which lowered the BCR activation threshold. This phenotype was linked to reduced lymphoid enhancer-binding factor 1 (LEF1) levels, a Wnt-responsive transcription factor, as HMGB1 directly bound the Lef1 promoter to sustain its transcription, thereby repressing Cd21 . Furthermore, HMGB1 constrained actin reorganization by suppressing the MST1/DOCK8/WASP axis, which feedback-modulated BCR clustering and signalosome recruitment. Collectively, HMGB1 ensures optimal BCR signaling by transcriptionally and cytoskeletally tuning activation thresholds, highlighting its dual role as a nuclear regulator and cytoskeletal modulator in B cell immunity.

IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33^-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33^-/- and WT mice after ON injury, but not in ST2^-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.

Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.

Purpose: IL-33 is constitutively expressed in skin tissues. Alopecia, a T cells-driven disorder of the hair follicles (HFs), is a common complication in the development of psoriasis. However, the role of IL-33 in psoriatic alopecia remains uncovered. Here, we investigated the roles of IL-33 in inducing pathological changes of hair follicles in psoriasis. Patients and Methods: Clinical samples and imiquimod (IMQ)-induced psoriatic mice samples were used to investigate the pathological changes and T-cell infiltration of HFs. By using immunohistochemistry staining, the distribution and expression alteration of IL-33 in HFs were determined. Next, by using IL-33 and ST2 knockout mice, we investigated the role of IL-33/ST2 axis in the pathological changes of HFs in psoriasis. Meanwhile, recombinant IL-33 protein was subcutaneous injected to confirm its effect. Finally, RNA sequencing was used to clarify the genes and signaling pathways that involved in this process. Differentially expressed genes were further verified by RT-PCR in cultured HFs in vitro. Results: We found that the pathological changes of HFs and T cells infiltration in imiquimod-induced psoriatic mice were similar to that in psoriasis patients. The IL-33 positive keratinocytes in the outer root sheath of HFs were increased in both psoriasis patients and psoriatic model mice compared with the controls. By using gene knockout mice, we found that the pathological changes and T cell infiltration were attenuated in IL-33^−/− and ST2^−/− psoriatic model mice. In addition, subcutaneous injection of recombinant IL-33 exacerbated the pathological changes of HFs and T cell infiltration. RNA sequencing and RT-RCR revealed that IL-33 upregulated the transcription of genes related to keratinocytes proliferation and T lymphocytes chemotaxis. Conclusion: Our study identifies that IL-33 promotes the pathological changes of HFs in psoriasis, which contributes to psoriatic alopecia. Inhibition of IL-33 may be a potential therapeutic approach for psoriatic alopecia.