Efferocytosis failure in chronic rhinosinusitis with nasal polyps: receptor-level mechanisms of unresolved type 2...

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prototypical type 2 airway disease in which tissue eosinophilia persists. That persistence is conventionally attributed to excess recruitment and to slowed apoptosis. Both explanations concern arrival and survival, and neither specifies what becomes of an eosinophil once it has died. That step is efferocytosis, the receptor-guided ingestion of apoptotic cells by macrophages, which differs from microbial phagocytosis in its ligands, its signaling output and its metabolic consequences. We establish this distinction first, because it decides which published datasets qualify as evidence and which do not. We then grade the surviving evidence and propose a cascade-anchored model in which failure is localized to three candidate lesions in the polyp macrophage: loss of an interleukin-10-dependent, MerTK-competent subset; a receptor repertoire skewed toward AXL and TIM-4 in which expression is uncoupled from productive ingestion; and an execution block at the phosphoinositide and Rac1 module. This model assigns the macrophage subsets reported in CRSwNP, including IL-10-deficient, ALOX15-positive, TIM-4-positive, TIPE2-positive, HMOX1-high and INPP4A-deficient populations, to defined steps rather than to a polarization label. We restate the shedding hypothesis as reduced surface receptor availability and reconcile a discordant tissue sheddase dataset. We explain why locally raised pro-resolving mediators cannot compensate when the receptor executing their action is absent, filter candidate therapies through the constraints of a colonized mucosal barrier, and note that the same receptors are targeted for inhibition in oncology. Finally, we specify the measurements that would refute the model.