Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Abstract

The human CD14 + monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16 + monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16 + CD163 + MerTK + pSTAT3 + phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16 + CD163 + MerTK + pSTAT3 + cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16 + C-D163 + MerTK + pSTAT3 + monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

“…NF-κB plays a critical role in IL-6 transcription in addition to AP-1, NF-IL-6 and STAT3. STAT3 was shown to be a key signaling molecule in Mtb infected macrophages2829 and macrophages with activated STAT3 in the peripheral blood of TB patients were shown to be pathogenic associated with TB progression57. Consistent with this, our Western blot results show that ESAT-6 induced STAT3 phosphorylation in macrophages (Fig.…”

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

“…Tuberculosis is associated with an expansion of immunomodulatory CD16 + monocyte population (39). Monocytes have been implicated in the establishment of Th17 response in autoimmune diseases (40, 41) and infection (42).…”

Macrophage heterogeneity and plasticity in tuberculosis

“…It was shown that circulating CD16+ monocytes isolated from TB patients had elevated cell surface expression of CD11b, TLR2, TLR5, CCR1, CCR2, and CCR5, and their ability to differentiate into DCs and induce T‐cell activation was compromised . Macrophages differentiated from these CD16+ monocytes were further shown to be skewed toward M2‐like activation status with elevated expression of CD163, MerTK, and STAT3 . The study concluded that during an active TB infection, human monocytes are predisposed to differentiate toward an anti‐inflammatory (M2‐like) macrophage activation program, exhibiting enhanced protease‐dependent motility, pathogen survival, and immuno‐modulatory properties.…”