Cell death provokes a robust inflammatory response. We have previously shown that this response is dependent on IL-α. Here we investigate the cellular mechanism used by a host to sense cell death, produce IL-α and also the role of IL-β in this response. In almost all cases examined, the IL-1 that stimulated the death-induced inflammatory response came from the host rather than the cell that was dying. In these situations, host bone marrow-derived cells were the key source of the IL-α that was required for the inflammatory response. Conditional cellular depletion and reconstitution in CD11b promoter- driven diphtheria toxin receptor transgenic mice revealed that host macrophages played an essential role in the generation of the inflammatory response and were the source of the required IL-α. In addition, we found a role for IL-β in the death-induced inflammatory response and that this cytokine was generated by both bone marrow-derived and radioresistant host cells. The one exception to these findings was that when dendritic cells were injected into mice, they provided a portion of the IL-1 that stimulated inflammation, and this was observed whether the dendritic cells were live or necrotic. Together, these findings demonstrate that macrophages play a key role as the primary sentinels that are required to sense and report cell death in ways that initiate the inflammatory response. One key way they accomplish this important task is by producing IL-α that is needed to initiate the inflammatory response.

In the present study, we have found that intestinal flora strongly influence peritoneal neutrophilic inflammatory responses to diverse stimuli, including pathogen-derived particles like zymosan and sterile irritant particles like crystals. When germ-free and flora-deficient (antibiotic-treated) mice are challenged with zymosan intraperitoneally, neutrophils are markedly impaired in their ability to extravasate from blood into the peritoneum. In contrast, in these animals, neutrophils can extravasate in response to an intraperitoneal injection of the chemokine, macrophage inflammatory protein 2. Neutrophil recruitment upon inflammatory challenge requires stimulation by microbiota through a myeloid differentiation primary response gene (88) (MyD88) -dependent pathway. MyD88 signalling is crucial during the development of the immune system but depending upon the ligand it may be dispensable at the time of the actual inflammatory challenge. Furthermore, pre-treatment of flora-deficient mice with a purified MyD88-pathway agonist is sufficient to restore neutrophil migration. In summary, this study provides insight into the role of gut microbiota in influencing acute inflammation at sites outside the gastrointestinal tract

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