Jana Neuber, Florens Lohrmann, Samuel Wald, Merve Göçer, Anne Kathrin Lösslein, David Obwegs, Manuel Rogg, Vitka Gres, Julia Kolter, Torsten Goldmann, Kerstin Walter, Christoph Hölscher, Christoph Schell, Sebastian Preissl, Sagar, and Philipp Henneke
Background & Aims
Kupffer cells (KCs), the prenatally seeded macrophages of the liver, show unique functional and immunophenotypic features among tissue-resident macrophages. They are considered as terminally differentiated with negligible cellular postnatal input. Their adaptability in disease is 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 unmask KCs as highly plastic cells, critical to responding to extreme environmental changes.
IMPACT AND IMPLICATIONS
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 KC respond with a unique and organ-specific program to chronic mycobacterial infections.
