IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease

Abstract

During mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mt) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mt. Accordingly, we showed that IL17A and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with Mt H37Rv or the mutant MtΔRD1. Patients with active disease were classified as high responder (HR) or low responder (LR) according to their T cell responses against Mt. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/ERK2-MAPK3/ERK1 but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 α both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients' monocytes, IL17A was unable to augment autophagy because of a defect in the MAPK1/3 signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mt, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen.

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

“…Among them, IL-17A and IL-17F share a similar structure and have similar roles in the immune response against Mtb infection. 10,11 The roles of other members of the IL-17 family are currently not known in Mtb infection.…”

Immunosuppressive role of PGE2 during human tuberculosis

“…Protection against necrosis (by preventing damage to the internal mitochondrial membrane 5 and promoting rapid repair of the plasma membrane 7 ) and the switch towards programmed cell death by apoptosis are key mechanisms in the resolution of the infection. We and other authors have demonstrated that activation of autophagy can result in the elimination of the bacteria in autolysosomes 14,29,30 . Furthermore, autophagy also controls inflammation by regulating signaling pathways of the innate immunity, removing endogenous agonists from the inflammasome and by modulating the secretion of immune mediators.…”

“…First, we performed a kinetic study in which the autophagy levels in stimulated-cells from HD and TB patients were evaluated by flow cytometry as described before 14 . As shown in Figure 5A and B, a significant increase in the percentage of CD14 + LC3A, B-II + monocytes and in the relative mean fluorescence intensity (rMFI) was detected in cells treated with PGE2 for 16 hours.…”

“…In vitro stimulation of cells was performed with a cell lysate from the virulent Intracellular staining of endogenous saponin-resistant LC3 was performed as described 14 . Briefly, cells were washed with PBS and then permeabilized with PBS containing 0.05% saponin.…”

Decreased phagocytic capacity accompanied by autophagy activation in blood monocytes of tuberculosis patients

“…Although intermediate CD14+CD16+ monocytes can promote microbial resilience, classical CD14+CD16-monocytes inhibit the intracellular growth of M. tuberculosis [20]. Moreover, interleukin 17A and vitamin D3 have been reported to enhance the autophagic action of monocytes against M. tuberculosis infection in vitro [21,22]. However, very few studies have determined the various stages of the activation or inhibition of circulating monocytes in tuberculosis patients.…”