Kupffer cell plasticity regulates hepatic immunity in mycobacterial infection.

BACKGROUND & AIMS: Kupffer cells (KCs), the prenatally seeded macrophages of the liver, display unique functional and immunophenotypic features among tissue-resident macrophages. They are considered terminally differentiated with negligible postnatal cellular input. Their adaptability in disease has thus been attributed to recruited, monocyte-derived KCs. Here, we explored KC plasticity and the impact of their ontogeny in persisting mycobacterial infections, which primarily target macrophages.

METHODS

Models of systemic chronic infection with Mycobacterium bovis or Mycobacterium avium were combined with genetic monocyte deficiency (Ccr2-/-, Irf8-/-), KC fate-mapping mice, bone marrow transplantation, high-resolution imaging and immunophenotyping. In addition, ATAC, bulk RNA, and single-cell RNA sequencing were conducted to specifically delineate origin, heterogeneity, and adaptations of KCs during infections.

RESULTS

Mycobacterial infections induced the emergence of a unique KC subset, which lacked the signature markers CLEC4F and VSIG4 ("KClow"). KClow were derived from embryonically seeded KCs and accumulated exclusively within hepatic granuloma cores. In contrast, monocyte-derived macrophages were localized at the granuloma periphery, yet contributed to the tissue reaction. We identified KClow as specialized antimycobacterial effector cells with a heightened ability to produce iNOS, adapted to a hypoxic microenvironment, and able to modulate adaptive immune responses. Despite their fundamental deviation from the classical KC phenotype, KClow showed remarkable plasticity. Monocytes, on the other hand, were crucial for granuloma initiation.

CONCLUSIONS

Mycobacterial infections reveal KCs as highly plastic cells that are critical for responding to extreme environmental changes.

IMPACT AND IMPLICATIONS: Kupffer cells (KCs) are traditionally regarded as terminally differentiated macrophages with limited plasticity, reliant on monocyte-derived KCs during liver infections or injury. In contrast, using a chronic mycobacterial infection model, we found tissue-resident KCs to be very plastic cells, which are strongly engaged in the antimycobacterial response and adopt a specific spatial distribution. These findings suggest that KCs respond with a unique and organ-specific program to chronic mycobacterial infections.