A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils

Abstract

Graphical AbstractHighlights d cDC1s regulate the magnitude of the innate immune response to cutaneous bacteria d cDC1s control neutrophil recruitment, survival, and functions in inflamed skin d Activated EpCAM + CD59 + Ly-6D + cDC1s control neutrophil biology via VEGF-a secretion d cDC1s secrete VEGF-a in a model of bacterial insult in human skin SUMMARY Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor a (VEGF-a) by a minor subset of activated EpCAM + CD59 + Ly-6D + cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Gué rin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.

DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

“…The administration of anti-DNGR-1 blocking antibodies recapitulates the increased neutrophil infiltration in WT but not in Batf3-deficient mice, which indicates that cDC1s are fundamental drivers of this phenotype (6). These results highlight the relevance of Batf3-dependent cDC1s in the regulation of neutrophil recruitment, which was corroborated in different models of bacterial infections in the skin, where a subset of activated cDC1s has been identified as responsible for driving neutrophil infiltration (51).…”

Dendritic Cells and Microglia Have Non-Redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

“…cDC1 play critical roles in inducing T helper 1 and cytotoxic T cell immunity because of their capacity to cross-present antigen (Hildner et al, 2008). Moreover, cDC1 regulate complex innate immune responses (Janela et al, 2019;Del Fresno and Sancho, 2019) that may contribute to their effect on stroke outcome. Under pathological conditions, several lines of evidence support the participation of cDC1 in induction of tolerance mediated by promoting inducible Treg cells in several experimental settings (Coombes et al, 2007;Sun et al, 2007;Toubai et al, 2010;Khare et al, 2013;Arnold et al, 2019).…”

Migration of intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

“…In this model, a floxed transcriptional termination cassette is inserted into the TLR3 gene (TLR3 OFF ), abolishing TLR3 expression. Expression of TLR3 by cDC1s could then be restored in cDC1.TLR3 ON mice in which the TLR3 stop codon was deleted using XCR1-driven cre recombinase (XCR1.cre (Janela et al, 2019)) ( Fig. 2B and Supplemental Fig.…”

“…Both male and female mice were used between 8 and 16 weeks of age as no obvious age differences were detected. CD11c.cre mice (B6.Cg-Tg(Itgax-cre)1-1Reiz/J (Caton et al, 2007)) allow floxed gene deletion in CD11c-expressing cells, huCD207.cre mice drive floxed gene deletion in Langerhans cells and intestinal cDC2 (Welty et al, 2013), XCR1.cre mice permit to specifically delete floxed genes in cDC1 (Janela et al, 2019), villin.cre (B6.Cg-Tg(Vilcre)997Gum/J) mice excise floxed genes in intestinal epithelial cells (Madison et al, 2002) and Rosa26-STOP-YFP mice allow tracking of cre specificity (B6.129X1-Gt(ROSA)26Sor tm1(EYFP)Cos /J). We used "switch-on" mutants carrying a floxed stop cassette in the endogenous locus prior to the gene of interest, allowing for re-expression of the targeted gene in the presence of cre for MyD88 (Gais et al, 2012), TLR3 and TRIF (unpublished, manuscript in preparation) (both generated at TU Munich, Germany).…”