Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

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Abstract
Bacterial infection triggers host inflammation through the activation of immune cells, leading to the elimination of bacteria. However, the regulatory mechanisms of the host inflammatory response remain unknown. Here we report that a subset of potent tolerogenic dendritic cells (DCs), regulatory DCs (DCregs), control the systemic inflammatory response. Unlike normal DCs, which produced proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS), DCregs produced fewer proinflammatory cytokines and instead preferentially produced interleukin-10 (IL-10), and these events involved the expression of IκBNS and Bcl-3 as well as cyclic AMP (cAMP)-mediated activation of protein kinase A (PKA). In addition, DCregs not only suppressed LPS-induced production of proinflammatory cytokines in macrophages, but also reduced their serum levels in mice. Furthermore, DCregs protected mice against the lethality induced by experimental endotoxemia and bacterial peritonitis. The inhibitory effect of DCregs against inflammatory responses involved the production of IL-10. On the other hand, naturally existing tolerogenic DC subsets producing IL-10, CD11clowCD45RBhigh DCs, also suppressed LPS-induced host inflammatory responses. Thus, a subset of tolerogenic DCs act as potential regulators of the host inflammatory response, and they might have preventive and therapeutic potential for the treatment of systemic as well as local inflammatory diseases.