Lipopolysaccharide impacts murine CD103⁺ DC differentiation, altering the lung DC population balance

Abstract

Conventional DCs are a heterogeneous population that bridge the innate and adaptive immune systems. The lung DC population comprises CD103+XCR1+ DC1s and CD11b+ DC2s; their various combined functions cover the whole spectrum of immune responses needed to maintain homeostasis. Here, we report that in vivo exposure to LPS leads to profound alterations in the proportions of CD103+XCR1+ DCs in the lung. Using ex vivo LPS and TNF stimulations of murine lung and spleen‐isolated DCs, we show that this is partly due to a direct downregulation of the GM‐CSF‐induced DC CD103 expression. Furthermore, we demonstrate that LPS‐induced systemic inflammation alters the transcriptional signature of DC precursors toward a lower capacity to differentiate into XCR1+ DCs. Also, we report that TNF prevents the capacity of pre‐DCs to express CD103 upon maturation. Overall, our results indicate that exposure to LPS directly impacts the capacity of pre‐DCs to differentiate into XCR1+ DCs, in addition to lowering their capacity to express CD103. This leads to decreased proportions of CD103+XCR1+ DCs in the lung, favoring CD11b+ DCs, which likely plays a role in the break in homeostasis following LPS exposure, and in determining the nature of the immune response to LPS.

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

“…Also, a higher migratory rate of cDC1s from the lung to the draining lymph nodes could take part in the observed decrease percentage of this population following P. aeruginosa exposure (Ho et al, 2011;Nakano et al, 2013). Supported by previously-published results (Brassard et al, 2019) and present data, we propose that under homeostatic conditions, newly-recruited lung pre-DCs acquire CD103 expression in response to GM-CSF stimulation through their final differentiation into cDCs. However, in the context of Gramnegative bacterial exposure, the interaction with the bacteria or LPS prevents CD103 mRNA synthesis resulting in lower GM-CSF-induced CD103 expression on cDC1s.…”

“…We also report a decrease in CD103 + XCR1 + cDC1 proportions and, in return, an increase in CD11b + Sirpa + cDC2 proportions (Figure 1C). These results indicate that, as observed previously with LPS (Brassard et al, 2019), P. aeruginosa modulates lung cDC populations in favor of the DC2/monocyte-derived DC population.…”

“…The commitment to the cDC1 or cDC2 lineage is defined before the pre-DCs stage, and can be influenced by peripheral inflammation ( Schlitzer et al., 2015 ; Grajales-Reyes et al., 2015 ; Meyer et al., 2018 ; Beshara et al., 2018 ; Brassard et al., 2019 ). Thus, we hypothesized that following i.n.…”

“…cDC precursors then leave the bone marrow at the pre-DC stage and migrate through the bloodstream to various organs such as the lung ( Liu et al., 2009 ). Pre-DCs committed to the cDC1 lineage do not express CD103 ( Brassard et al., 2019 ). The exact mechanisms by which cDC1s acquire CD103 expression upon their entrance in the lung remain unclear, but in vivo and in vitro studies suggest that exposure to GM-CSF, present in the lung, is a potent inducer of cDC CD103 expression ( King et al., 2010 ; Greter et al., 2012 ; Mayer et al., 2014 ).…”

“…These distinctive roles for cDC1s and cDC2s in the response to bacteria suggest that the tight balance between cDC lung subsets is important to support effective local immune responses. Recently, we demonstrated that lung exposure to lipopolysaccharide (LPS), which induces a strong local and peripheral inflammatory response, modulates the proportions of cDC populations by decreasing the percentage of CD103 + cDC1s and increasing CD11b + DC proportions ( Brassard et al., 2019 ). Since LPS is one of multiple bacterial components that may influence cDC populations and with the potential crucial role of cDC1s in the fight against bacterial infections in the lung, the impact of whole bacteria on the lung cDC signature remained an important unanswered question.…”