Dendritic Cells Coordinate Innate Immunity via MyD88 Signaling to Control Listeria monocytogenes Infection

Abstract

Listeria monocytogenes (LM), a facultative intracellular Gram-positive pathogen, can cause life-threatening infections in humans. In mice, the signaling cascade downstream of the myeloid differentiation factor 88 (MyD88) is essential for proper innate immune activation against LM, as MyD88-deficient mice succumb early to infection. Here, we show that MyD88 signaling in dendritic cells (DCs) is sufficient to mediate the protective innate response, including the production of proinflammatory cytokines, neutrophil infiltration, bacterial clearance, and full protection from lethal infection. We also demonstrate that MyD88 signaling by DCs controls the infection rates of CD8α(+) cDCs and thus limits the spread of LM to the T cell areas. Furthermore, in mice expressing MyD88 in DCs, inflammatory monocytes, which are required for bacterial clearance, are activated independently of intrinsic MyD88 signaling. In conclusion, CD11c(+) conventional DCs critically integrate pathogen-derived signals via MyD88 signaling during early infection with LM in vivo.

MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium

“…Importantly, this gain-of-function model restricts functional MyD88 signaling to a given Cre-expressing cell or tissue type, while all other cells of the body remain deficient for MyD88. We and others have shown that this recently developed MyD ON model allows the precise study of direct consequences of cell type-specific TLR/IL-1R-mediated signaling on the immune response [31, 59–62]. …”

The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes

“…Mice with MyD88 expression exclusive to dendritic cells responded comparably to wild-type mice during infection with L. monocytogenes (89). These data suggest that MyD88 is required in dendritic cells for optimal responses to L. monocytogenes but neutrophil recruitment and function are independent of MyD88 signaling.…”

Inflammatory monocyte effector mechanisms

“…Of note, while all these studies clearly demonstrate the presence of specific TLRs and functional activation pathways intrinsically present in Ly6C + monocytes and involved in regulating their differentiation into iNOS + and/or TNFα + cells, and potent APCs, none of them formally established their cell-intrinsic requirements. In line with this interpretation, a very recent report by the Sparwasser group utilized elegant gain of function experiments in which a 'floxed-STOP' cassette was inserted upstream of the MyD88 adaptor, preventing its expression, unless when the Cre recombinase was expressed (17). Functional MyD88 expression in CD11c + DCs only, with lack of MyD88 in all other cells, was sufficient to orchestrate Ly6C + monocytes differentiation into Tip-DCs during Lm infection, establishing that cell-intrinsic expression of MyD88 by Ly6C + monocytes may not be required.…”

“…While the formal demonstration that TNF-α and/or NO production by Ly6C + monocytes indeed represents the mechanism of Lm clearance, the current body of work does provide conclusive evidence for this interpretation. Investigating further the mechanism of production of these key mediators, the recent data from the Sparwasser group have suggested that Ly6C + monocytes can differentiate into Tip-DCs with no cell-intrinsic requirement for MyD88 (17). Results from the Locksley lab have proposed that NK-cell derived IFN-γ - themselves activated in response to cDCs-derived IL-12- is essential for Ly6C + monocyte maturation into Tip-DCs (41), a result in agreement with our own data establishing the key function of IFN-γ in promoting Ly6C + monocyte differentiation during recall infection with Lm (43).…”