Efferocytosis-Driven M2 Macrophage Impairs Fibrotic Encapsulation and Promotes Echinococcus multilocularis Growth in Cotton Rats (Sigmodon hispidus)

Alveolar echinococcosis, caused by Echinococcus multilocularis, exhibits significant species-dependent susceptibility. This study compared the early hepatic tissue responses to E. multilocularis in highly susceptible cotton rats (Sigmodon hispidus) and laboratory mice (DBA/2 and AKR/N). Following oral administration of E. multilocularis eggs, cotton rats developed a greater number of hepatic lesions within 2 weeks, whereas mice required 4 weeks to develop smaller lesions. Histopathology revealed accelerated multilocular cyst formation in cotton rats. Unlike mice, which formed dense collagenous layers isolating cysts, cotton rats lacked adventitial layers despite similar fibrotic thickness. Immunohistochemistry revealed abundant CD206+ macrophages at cyst peripheries in cotton rats, engaging in efferocytosis of apoptotic neutrophils with expression of TGF-β, galectin-3, and VEGF. Efferocytic macrophages expressed collagen-degrading enzymes (cathepsin K and MMP9) and the growth factor FGF2. These findings suggest that efferocytosis by neutrophils drives macrophages toward an anti-inflammatory M2 phenotype, leading to immune evasion, ineffective fibrotic encapsulation, and parasitic growth. Given the wide distribution of cotton rats in the Americas and the expanding range of E. multilocularis, their hypersusceptibility raises significant public health concerns as rodents could serve as an intermediate host. These insights may inform new strategies for host-parasite interactions and the control of alveolar echinococcosis.