Lesion-specific features of macrophage polarization contribute to Mycobacterium tuberculosis infection in the lungs of patients with pulmonary tuberculosis.

BACKGROUND: The innate immunity, linked to macrophage polarization, plays a critical role in the progression of tuberculosis (TB) disease caused by M. tuberculosis (Mtb) infection. Within a single patient with active pulmonary TB, Mtb infection leads to the formation of extensive lung pathology with a spectrum of morphologically and physiologically distinct TB lesions at different stages of progression, where macrophages are believed to represent varying functional phenotypes. Understanding the dynamics of macrophage polarization with identification of the cytokine network, molecular pathways, and polarizing stimuli in the lung TB lesions of patients, depending on various aspects of the host-pathogen interactions, is crucial for developing better treatment strategies, based on immune-modulatory therapeutic approaches, especially in the context of the ongoing spread of drug-resistant TB.

METHODS: The expression of pro-inflammatory/anti-bacterial M1 cytokines (IFNγ, TNFα, IL-1β, and IL-12) and anti-inflammatory/immunosuppressive M2 cytokines (IL-4, IL-10, and FGF2) as well as activation of the AhR and NF-κB pathways were estimated in an immunofluorescence assay and analyzed in relation to Mtb infection in macrophages in the ex vivo cell cultures and/or on the histological sections obtained from various lung TB lesions of the same patients (n = 25) with clinically active pulmonary, predominantly drug-resistant TB.

RESULTS: Macrophage polarization was determined by local tissue microenvironments with varying fibrosis severity but was independent of Mtb's genetic and phenotypic diversity in human lungs, the anti-TB treatment of patients before surgery and AhR signaling activity in smoker's macrophages. Pathogen control (without complete Mtb clearance) correlated with co-expression of cytokines of both cytokine types in the mixed M1/M2-polarized macrophages and, presumably, with NF-κB-mediated activation of smoker's alveolar macrophages in the lung TB lesions with local/minimal fibrosis and the preserved alveoli. In contrast, suppressed macrophages (lacking cytokine production and NF-κB-activated mediators and, in parallel, harboring higher Mtb loads) exhibited an M0-like polarization state in tuberculoma walls and extensively fibrotic lung tissues.

CONCLUSIONS: The host cells' inability to eradicate Mtb reflected suboptimal development of the immune responses in the patients' lungs. Defining the complexity and functional diversity of macrophage phenotypes and signaling pathways involved in the pathogen control and tissue pathology across various lung TB lesions within the same patients with pulmonary TB is essential for designing novel host-directed therapies that modulate the patients' immune responses to optimize protection against Mtb infection and prevent the pathogen transmission.