Macrophage Differentiation and Metabolic Adaptation in Mycobacterial Infections

The adaptation of macrophages—the most common tissue-resident immune cells—to metabolic and microbial cues with high local variability is essential for the maintenance of organ integrity. In homeostasis, macrophages show largely predictable tissue-specific differentiation, as recently revealed by multidimensional methods. However, chronic infections with human-adapted pathogens substantially contribute to the differentiation complexity of tissue macrophages, which has been only partially resolved. Specifically, the response to mycobacterial species—which range from Mycobacterium tuberculosis (with highest specificity for humans, broad organ tropism, yet tissue-specific disease phenotypes) to environmental mycobacteria with humans as accidental hosts—may serve as a paradigm of tissue macrophage adaptation mechanisms. While mycobacterial species-specific tissue preferences are partially related to the mode of acquisition and pathogen characteristics, evolutionary convergence with macrophages driven by metabolic features of the target organ likely contributes to infection resistance and immunopathology. In this review, we unravel the mechanisms of tissue-specific macrophage differentiation and its limitations in mycobacterial infections.