Exposure to the Gram-Negative Bacteria Pseudomonas aeruginosa Influences the Lung Dendritic Cell Population Signature by Interfering With CD103 Expression

Abstract

Lung dendritic cells (DCs) are divided into two major populations, which include CD103+XCR1+ cDC1s and CD11b+Sirpα+ cDC2s. The maintenance of their relative proportions is dynamic and lung inflammation, such as caused by exposure to lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, can have a significant impact on the local cDC signature. Alterations in the lung cDC signature could modify the capacity of the immune system to respond to various pathogens. We consequently aimed to assess the impact of the Gram-negative bacteria Pseudomonas aeruginosa on lung cDC1 and cDC2 populations, and to identify the mechanisms leading to alterations in cDC populations. We observed that exposure to P. aeruginosa decreased the proportions of CD103+XCR1+ cDC1s, while increasing that of CD11b+ DCs. We identified two potential mechanisms involved in this modulation of lung cDC populations. First, we observed an increase in bone marrow pre-DC IRF4 expression suggesting a higher propensity of pre-DCs to differentiate towards the cDC2 lineage. This observation was combined with a reduced capacity of lung XCR1+ DC1s to express CD103. In vitro, we demonstrated that GM-CSF-induced CD103 expression on cDCs depends on GM-CSF receptor internalization and RUNX1 activity. Furthermore, we observed that cDCs stimulation with LPS or P. aeruginosa reduced the proportions of intracellular GM-CSF receptor and decreased RUNX1 mRNA expression. Altogether, these results suggest that alterations in GM-CSF receptor intracellular localization and RUNX1 signaling could be involved in the reduced CD103 expression on cDC1 in response to P. aeruginosa. To verify whether the capacity of cDCs to express CD103 following P. aeruginosa exposure impacts the immune response, WT and Cd103-/- mice were exposed to P. aeruginosa. Lack of CD103 expression led to an increase in the number of neutrophils in the airways, suggesting that lack of CD103 expression on cDC1s could favor the innate immune response to this bacterium.

Microbial Community Establishment, Succession, and Temporal Dynamics in an Industrial Semi-Synthetic Metalworking Fluid Operation: A 50-Week Real-Time Tracking

“…Such endotoxin-based assessment of the burden of Gram-negative organisms such as Pseudomonas as well as high endotoxin levels may be significant in the assessment of machine workers’ risk of occupational lung disease. In this context, several studies have associated lung inflammatory response in machine workers with exposure to microbial endotoxins and antigens in the machining fluid [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Initial studies on the etiology of hypersensitivity pneumonitis (HP) in machinists implicated Pseudomonas as the etiological agent [ 67 ], and later studies from our laboratory have shown exacerbating effects of Pseudomonas in MWF mycobacteria-induced HP-like pathology in mice (unpublished).…”

“…SDA meant for the growth of fungi did not yield any fungal colonies from the first three DCR samples (before dump, neat, and non-circulated) and SS#1. However, fungal population was detected in the subsequent samples except SS#6, 7, 12,13,14,17,18,21,23,24,28,29,31,33,34, and 37 at levels varying from 1 to 3.25 × 10 3 cfu/mL. The typical fungal colonies were identified as N. haematococca based on ITS sequencing.…”

“…Studies have implied cross-pollination of microbial agents between MWF and human cases of respiratory disease [ 19 , 23 ]. The microbial agents and their products such as antigens and endotoxins released in these fluids have been linked with induction of an inflammatory response in MWF-exposed machine workers [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ] and animal models [ 34 , 35 , 36 ]. The microbial antigens may be contributed by culturable, non-culturable, and non-viable microorganisms.…”

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response

“…Limited work has investigated the roles of DCs in chronic P. aeruginosa infection, but they are known to be activated and express co-stimulatory molecules CD80 and CD86 in the lung and regional lymph nodes in response to P. aeruginosa ( 210 ). Furthermore, P. aeruginosa appears able to modulate DC subpopulations, resulting in a skewing of the resting conventional DC (cDC) population toward cDC2s that support a Th2 response rather than cDC1s that promote Th1 and bacterial clearance ( 211 ). This fits into the existing paradigm of Th2-skewed immunity in chronic P. aeruginosa and suggests that DCs may be contributing to this later T cell imbalance.…”

Countering the advert effects of lung cancer on the anticancer potential of dendritic cell populations reinstates sensitivity to anti-PD-1 therapy

“…This may stem in part from the current lack of knowledge on the impact of lung cancer on local DC populations, which are crucial in anticancer immunity. Previous studies by our group suggested that various inflammatory contexts profoundly impact the local DC signature, as well as disease progression [ 8 , 9 , 19 ]. Specifically, we demonstrated that the proportions of CD103 + DC1s are drastically reduced under inflammatory conditions.…”