Biomed Pharmacother. 2016 Feb;77:129-34.

IL-17A and IL-17F induce autophagy in RAW 264.7 macrophages

László Orosz1, Elena Gouitel Papanicolaou1, György Seprényi2, Klára Megyeri1

1Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, H-6720 Szeged, Dóm tér 10., Hungary

2Department of Medical Biology, Faculty of Medicine, University of Szeged, Somogyi Béla u. 4, Szeged, Hungary



Autophagy is an important cellular catabolic process for the lysosomal degradation of cytoplasmic organelles, proteins and microorganisms. The autophagic process is intertwined with the immune response: autophagy regulates both innate and adaptive immunity, conversely, cytokines produced during the course of the immune response modulate various functions of the autophagic cascade. The IL- 17 family member cytokines play a pivotal role in immune protection against extra- and intracellular bacterial pathogens. Since the effects of IL-17A and IL-17F on autophagy have not yet been reported, we have evaluated the autophagic activity in the RAW 264.7 cell line treated with either IL-17A or IL-17F. Both IL-17A and IL-17F proved to promote microtubule-associated protein 1 light chain 3 B-II (LC3B-II) accumulation, enhance the autophagic flux, facilitate the intracellular redistribution of LC3B, increase both the average number and the size of autophagosomes per cell, and foster the formation of acidic vesicular organelles. IL-17F was considerably more efficient than IL-17A in promoting the autophagic process. Further experiments to determine the potential effect of IL-17-induced autophagy on the antibacterial activity of RAW macrophages revealed that IL-17F significantly decreased the intracellular counts of Mycobacterium terrae, while the colony-forming unit values remained comparable in the IL- 17A-treated cells and the control cultures. In conclusion, these results demonstrate that IL-17A and IL-17F are capable of inducing autophagy in macrophages, and thereby contribute to the elimination of Mycobacterium terrae. These data may bear on the pathogenesis of infections caused by Mycobacterium terrae, as IL-17 plays a pivotal role in the immune response to mycobacteria. IL-17-mediated activation of autophagy may also be implicated in various infections and other pathological conditions.

KEYWORDS: Autophagy; IL-17A; IL-17F; Macrophage; Mycobacterium terra

PMID: 26796276



Autophagy plays a pivotal role in antimicrobial defense by targeting pathogenic microorganisms for lysosomal degradation [1, 2]. The autophagic clearance of microbes is termed xenophagy [1, 2]. A growing body of evidence indicates that numerous bacteria and viruses withstand the destructive force of autophagy, or even harness this cellular catabolic pathway for their own benefit [3]. The courses of infections are strongly influenced by various other cellular processes, inflammatory mediators, cytokines and metabolic conditions [1]. Thus, autophagy is regulated intricately by diverse stimuli. Using IL-17, we observed intensified autophagic activity, and increased elimination of Mycobacterium terrae in the RAW 264.7 macrophages. In view of these data, it is tempting to speculate that IL-17-driven autophagy may have the potential to alter the course of infections caused by other pathogens.

It is reasonable to infer that in those infections, when autophagy destroys the invading microbes, IL-17-mediated stimulation of the autophagic cascade may play a significant protective role by facilitating the rapid and efficient elimination of viruses or bacteria, such as Sindbis virus, Rift Valley fever virus, and vesicular stomatitis virus or Pseudomonas aeruginosa and Klebsiella pneumoniae [4, 5] (Fig. 1).

In contrast, in infections caused by microorganisms that escape from recognition by the autophagic machinery, IL-17 may restrict the survival of pathogens only to some extent, and can easily override autophagy culminating in cell demise. Bacteria that elude autophagy are numerous, exemplified by Salmonella typhimurium, Mycobacterium tuberculosis strain H37Rv, Mycobacterium marinum, Bacillus anthracis, Vibrio cholerae, Shigella flexneri, Listeria monocytogenes, Francisella tularensis, Burkholderia pseudomallei, Yersinia enterocolitica, adherent-invasive Escherichia coli, and Orientia tsutsugamushi [3] (Fig. 1). Herpes simplex viruses and human cytomegalovirus trigger autophagy, but can also counteract this important catabolic cellular process [4] (Fig. 1).

Several other bacteria possess the remarkable ability to co-opt autophagy in order to support their intracellular survival and growth (Fig. 1). This strategy is exemplified by Streptococcus pyogenes, Staphylococcus aureus, Anaplasma phagocytophilum, Mycobacterium tuberculosis strain Erdman, uropathogenic E. coli, Serratia marcescens, Yersinia pseudotuberculosis, Brucella species, Legionella pneumophila, Porphyromonas gingivalis, Coxiella burnettii, Chlamydophila trachomatis [3] (Fig. 1). Several viruses, including rubella virus, hepatitis B virus, hepatitis C virus, dengue virus, poliovirus, coxsackie B virus, coronaviruses, measles virus, human parainfluenza virus 3, influenza A virus, HIV-1, and the rotavirus likewise endowed with the capability to usurp certain elements of autophagy [4] (Fig. 1). IL-17 in infections caused by microorganisms that hijack autophagy may even be harmful for the host cells via enhancing multiplication of the pathogens.

However, future studies are needed to shed light on the precise role of IL-17-driven autophagy in each infection.



Figure 1: The hypothetical role of IL-17-mediated autophagy in various infections



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