Pseudomonas aeruginosa accentuates inflammatory responses under HIV infection through TREM‐1 activation

Abstract

ObjectiveHuman immunodeficiency virus (HIV) threatens human health worldwide. Anti‐retroviral therapy (ART) extends survival but does not eliminate HIV from its cellular reservoirs. Patients accepting ART show altered immunity and immune activation, and continue to present increased risk of bacteria associated pneumonia, which is a major cause of morbidity and mortality. As an important opportunistic human pathogen, Pseudomonas aeruginosa causes a wide variety of severe nosocomial infections. Triggering receptor expressed on myeloid cells‐1 (TREM‐1) is an amplifier of inflammation, and has been recognized as a critical immunomodulator in inflammatory diseases of both infectious and non‐infectious etiologies. However, molecular mechanisms underlying the functional role of TREM‐1 in lung infections of HIV patients remains to be defined.MethodsWild type C57 BL/6J and HIV transgenic mice were treated with P. aeruginosa strain PAO1 through intranasal administration, mouse lung injury status was observed through Hematoxylin and Eosin (H&E) staining. Total RNA of lung tissues was isolated, real‐time RT‐PCR and western immunoblots were performed to quantify gene and protein expression. THP‐1 derived macrophages and human monocyte‐derived macrophages were treated with recombinant HIV viral proteins Tat and gp120, expression of miR‐155 and SOCS1 were quantified, and oxidative phosphorylation (OXPHOS) was measured through mitostress assay. Co‐culture model was used to analyze intracellular communications between macrophage and lung epithelial cells, and exosomes secreted by macrophages were isolated and cocultured with recipient cells, then expression of key tight junction proteins involved in epithelial barrier function were analyzed.ResultsCompared to wild type control, PAO1 accentuates acute neutrophilic inflammation in HIV transgenic mice with increase in neutrophil influx, expression levels of TREM‐1 and proinflammatory cytokines, particularly IL‐1β, TNF‐α and IL‐6. TREM‐1 silencing in macrophages exposed to HIV‐related proteins Tat or gp120, resulted in significant attenuation of miR‐155 expression with increased SOCS1 expression, and reduced mitochondrial reactive oxygen species (mtROS) and elevated oxygen consumption rate (OCR). Furthermore, TREM‐1 silencing in Tat‐treated macrophages reversed the disruption of tight junction barrier integrity in co‐cultured lung epithelial cells through modulation of macrophage‐derived exosome shuttling.ConclusionTREM‐1 escalates neutrophilic lung inflammation in HIV transgenic mice treated with PAO1, results in mitochondrial dysfunction of macrophages and disrupts tight junction barrier integrity of epithelia cells in lung microenvironment. These data suggest that TREM‐1 inhibition might be an important immunomodulatory therapeutic strategy for HIV‐infected patients with lung infections.Support or Funding InformationThis work is supported by VA Merit Review 2I01BX001786‐06A1 (Ruxana T Sadikot) and R01 HL125042(David M Guidot).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.