TL1A morphological shifts and inflammatory heterogeneity in rhinosinusitis and allergic rhinitis: a hypothesis-driven review.

Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are heterogeneous upper-airway inflammatory disorders in which type 2 inflammation is common but does not fully explain all clinical endotypes or treatment responses. This review synthesizes evidence on tumor necrosis factor-like ligand 1A (TL1A) and considers whether its membrane-bound (mTL1A) and soluble (sTL1A) forms could connect epithelial injury, macrophage activation, and mixed inflammatory networks. Evidence from intestinal and lower-airway models supports TL1A/DR3 signaling in several immune contexts, while sinonasal studies provide only limited, cell-specific evidence and do not yet establish local TL1A abundance, shedding dynamics, or a complete macrophage-centered feedback loop. We therefore propose a testable model in which mTL1A may support contact-dependent signaling, whereas epithelial stress and protease-mediated shedding may generate soluble TL1A with broader paracrine activity. In this framework, TL1A could cooperate with IL-33, TSLP, and IL-25 and might activate macrophage-dependent relays involving CXCL8/IL-8 and IL-1beta. Because neutrophils are generally considered indirect targets of TL1A/DR3 signaling, such relays could contribute to mixed or treatment-refractory inflammation without implying that TL1A alone is sufficient. The model provides a conceptual framework for integrating endotypic heterogeneity and identifying testable biomarkers and therapeutic hypotheses, but direct validation in human sinonasal tissue, nasal lavage fluid, and relevant experimental models remains necessary.