| Disease Introduction Mechanism | Fungal keratitis (FK) is a keratopathy with high blindness rate, which caused by pathogenic fungal infection. Failure to diagnose and treat in time will lead to corneal perforation, blindness, and even eyeball removal [1]. The immune function of organism is now considered to be closely related to fungal infection and disease progression. Thus, in-depth study of the corneal immune defense system is of great theoretical value for searching effective ways of corneal anti-fungal infection. Corneal epithelial cells (CECs) are the first innate immunity of cornea against fungi. CECs recognize pathogen-associated molecular pattern molecules (PAMPs) on the surface of pathogenic microorganisms through pattern recognition receptors (PRRs). Then, a series of signal transduction pathways such as NF-κB are activated, and the expression of inflammatory mediators and antibacterial peptides are increased, including IL-1β, IL-6, IL-8, TNF-α, hBD-2, and LL37, thereby exerting immunity response. Thymic stromal lymphopoietin (TSLP) is a kind of inflammatory factor similar to IL-7 that mainly produced by epithelial cells. TSLP is widely involved in immune responses mediated by natural killer cells, B lymphocytes, T lymphocytes, and dendritic cells (DCs) by binding to the TSLP receptor (TSLPR). Previous study has shown that CECs mainly induce TSLP expression through TLRdependent innate immune response. It has been confirmed that TSLP is associated with FK. Aspergillus fumigatus (A. fumigatus) induces the expression and secretion of TSLP in theCECs and cornea tissues ofmice. On the one hand, TSLP upregulation participates in the immune response of CECs by activating TSLPR/STAT5 and TLR2/MyD88/NF-κBp65 signaling pathways . On the other hand, TSLP upregulation promotes lymphocyte proliferation by upregulating the costimulatory factor CD69, activating CD4+ T cells, CD8+ T cells, and B lymphocytes, and inducing Th2-type polarization of CD4+ T cells. Previous study has found that TSLP activates DCs and promotes OX40L secretion by interacting with TSLPR on the surface of DCs. Subsequently, OX40L interacts with OX40 receptor on T lymphocytes to promote T cell proliferation and Th2-type immune response. The study of Cui et al. has confirmed that Pseudomonas aeruginosa infection induces TSLP expression in CECs and corneal tissues of mice, and neutralization of TSLP aggravates keratitis and promotes neutrophil infiltration. Although TSLP participates in the immune response of FK, its mechanism of action in the corneal anti-fungal immune response remains to be elucidated. After fungal infection, innate immune cells such as macrophages are activated by recognizing the corresponding PAMPs on the bacteria. On the one hand, the intracellular bactericidal system directly kills the fungus, and on the other hand, it produces a variety of cytokines and chemokines to regulate the immune inflammatory response. Appropriate inflammatory response is helpful for the organismto eliminate pathogenic bacteria, but excessive inflammatory response can cause tissue immune pathological damage. Thus, the precise regulation of inflammatory response is very important in anti-infective immunity. In addition to exogenous PAMPs, PRRs sense some endogenous danger signals, damage-associated molecular patterns (DAMPs), and participate in regulating the activation of immune response and inflammation. DAMPs include NLRP1, NLRP3, NLRC4, and AIM2, which are involved in the assembly and activation of inflammasomes, and the cleavage, maturation, and release of caspase-1 and IL-1β. The activated caspase-1 can induce a specific programmed death between apoptosis and necrosis, pyroptosis. Qu et al. have found that TREM2 knockdown induces caspase-1-depemdent pyroptosis, and caspase-1 inhibitor improves the corneal pathology in TREM2 silenced mice by inhibiting pyroptosis. It shows that pyroptosis is associated with keratitis. Therefore, we speculate whether TSLP secreted by CECs can regulate macrophage pyroptosis. Futher explore which inflammasomemediated pyroptosis is regulated by TSLP. |
