Abstract
Alveolar Macrophages play a key role in the development of a robust adaptive immune response against the agent of Tuberculosis (TB), Mycobacterium tuberculosis (M.tb). However, macrophage response is often hampered by the production of IL-10, a potent suppressor of the host immune response. The secretion of IL-10 correlates with TB pathogenesis and persistence in host tissues. Concordantly, inhibition of IL-10 signaling, during BCG vaccination, confers higher protection against M.tb through a sustained Th1 and Th17 responses. Therefore, uncovering host effectors, underlying mycobacteria-induced expression of IL-10, may be beneficial toward the development of IL-10-blocking tools to be used either as adjuvants in preventive vaccination or as adjunct during standard treatment of TB. Here, we investigated the role of FOXO3 transcription factor in mycobacteria-induced secretion of IL-10. We observed that PI3K/Akt/FOXO3 axis regulates IL-10 expression in human macrophages. Knocking down of FOXO3 expression resulted in an increase of IL-10 production in BCG-infected macrophages. The gene reporter assay further confirmed the transcriptional regulation of IL-10 by FOXO3. In silico analysis identified four Forkhead binding motifs on the human IL-10 promoter, from which the typical FOXO3 one at position −203 was the major target as assessed by mutagenesis and CHIP binding assays. Further, we also observed a decrease in gene expression levels of the M1 typical markers (i.e., CD80 and CD86) in SiFOXO3-transfected macrophages while activation of FOXO3 led to the increase in the expression of CD86, MHCI, and MHCII. Finally, co-culture of human lymphocytes with siFOXO3-transfected macrophages, loaded with mycobacterial antigens, showed decreased expression of Th1/Th17 specific markers and a simultaneous increase in expression of IL-4 and IL-10. Taken together, we report for the first time that FOXO3 modulates IL-10 secretion in mycobacteria-infected macrophage, driving their polarization and the subsequent adaptive immune response. This work proposes FOXO3 as a potential target for the development of host-directed strategies for better treatment or prevention of TB.
Highlights
Tuberculosis (TB) remains one of the top causes of death with an estimated 1.4 million deaths and 10.4 million new cases worldwide [1]
We have previously reported that BCG-mediated apoptosis of human macrophages relies on Forkhead box-O3 (FOXO3) activation, which is negatively regulated by the survival pathway PI3K/Akt [29]
We show that FOXO3 inhibits IL10 secretion in BCG-infected macrophage through the direct binding to and repression of IL-10 promoter, pushing the balance of the immune response toward an M1/Th1 phenotype
Summary
Tuberculosis (TB) remains one of the top causes of death with an estimated 1.4 million deaths and 10.4 million new cases worldwide [1]. Phagocytosis of mycobacteria initiates a series of innate and adaptive immune responses to contain the infection [6]. Macrophagederived cytokines, such as TNF-α, IL-12, and IL-1 family members as well as chemokines and antimicrobial peptides (AMPs) are critical for host anti-mycobacterial defense and shaping the disease progression [7]. Several studies have shown that IL-10 plays an important role in shaping the initial immune response and its expression level determines the fate of mycobacterial infections. It has been shown that IL-10 affects antigen procession and T cells priming by downregulating the expression of the major histocompatibility complex class II, CD80, CD86, and CD11c in BCG-infected macrophages and DC [12, 13]. M.tb-induced IL-10 promotes M2 macrophages polarization, which displays dampened antimycobacterial response [16]
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