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Immunity. 2015 Jan 20;42(1):145-58. doi: 10.1016/j.immuni.2014.12.020. Epub 2014 Dec 25.

Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection.

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Institut Pasteur, Biology of Infection Unit, 75015 Paris, France; Inserm U1117, 75015 Paris, France.
Institut Pasteur, Human Histopathology and Animal Models Unit, 75015 Paris, France.
Institut Pasteur, Lymphoid Tissue Development Unit, 75015 Paris, France.
Institut Pasteur, Biology of Infection Unit, 75015 Paris, France; Inserm U1117, 75015 Paris, France; Institut Pasteur, French National Reference Center and World Health Organization Collaborating Centre on Listeria, 75015 Paris, France; Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Division of Infectious Diseases and Tropical Medicine, Necker-Pasteur Centre for Infectiology, Necker-Enfants Malades University Hospital, 75015 Paris, France. Electronic address:


Kupffer cells, the phagocytes of fetal origin that line the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, we found that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, which was followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer cell death also triggered a type 2 response that involved the hepatocyte-derived alarmin interleukin-33 (IL-33) and basophil-derived interleukin-4 (IL-4). This led to the alternative activation of the monocyte-derived macrophages recruited to the liver, which thereby replaced ablated Kupffer cells and restored liver homeostasis. Kupffer cell death is therefore a key signal orchestrating type 1 microbicidal inflammation and type-2-mediated liver repair upon infection. This indicates that beyond the classical dichotomy of type 1 and type 2 responses, these responses can develop sequentially in the context of a bacterial infection and act interdependently, orchestrating liver immune responses and return to homeostasis, respectively.

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