Immunomodulatory properties of prostaglandin E2 on human neutrophils tuberculosis infection

Abstract

During Mycobacterium tuberculosis (Mtb) infection, neutrophils are among the first cells that migrate to the infectious focus and represent the most abundant cell population harboring Mtb in samples from patients with active tuberculosis (TB). Neutrophilic infiltration and exuberant inflammation represent characteristic features of severe TB, but neutrophil biology during TB remains poorly understood. Prostaglandin E2 (PGE2), an active lipid compound, is a key mediator of immunopathology in chronic infections . Manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of TB patients, but very limited information is available regarding this pathway in TB patients. The aim of this work was to investigate the role of PGE2 on the modulation of human neutrophil immune responses against Mtb. We detected a significantly higher number of neutrophils in patients with positive Acid Fast Bacilli (AFB) in sputum as compare to negative AFB TB patients (p<0.01). Besides, stimulation of neutrophils from healthy donors (HD) with an Mtb lysate (Mtb-Ag, 10μg/ml) significantly enhanced CD11b expression, a marker of neutrophil activation. Interestingly, CD11b levels were markedly reduced by effect of PGE2 (2 μg/ml). Furthermore, for the first time to our knowledge, we observed that neutrophils from HD and TB patients express SLAMF1, a costimulatory molecule recently described as a microbial sensor. Also, Mtb-Ag stimulation significantly increased the percentage of SLAMF1+ neutrophils (p<0.05), but PGE2 treatment diminished SLAMF1 levels (p<0.05). Moreover, neutrophils stimulated with Mtb-Ag augmented LC3B-II levels as compared to non-stimulated cells. Importantly, PGE2 treatment significantly increased autophagy flux in human neutrophils stimulated with Mtb-Ag (p<0.05). Therefore, autophagy, a process involved in the defense against Mtb, might prevent excessive inflammation and tissue damage. Taken together, our findings extend the information about the mechanisms mediated by PGE2 that operate during the human immune response to Mtb.