Zigmond, E. et al., 2014.
Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis.
Immunity, 40, pp.720-33.
AbstractInterleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Ralpha) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.
Newson, J. et al., 2014.
Resolution of acute inflammation bridges the gap between innate and adaptive immunity.
Blood, 124, pp.1748-64.
AbstractAcute inflammation is traditionally characterized by polymorphonuclear leukocytes (PMN) influx followed by phagocytosing macrophage (Mphis) that clear injurious stimuli leading to resolution and tissue homeostasis. However, using the peritoneal cavity, we found that although innate immune-mediated responses to low-dose zymosan or bacteria resolve within days, these stimuli, but not hyperinflammatory stimuli, trigger a previously overlooked second wave of leukocyte influx into tissues that persists for weeks. These cells comprise distinct populations of tissue-resident Mphis (resMphis), Ly6c(hi) monocyte-derived Mphis (moMphis), monocyte-derived dendritic cells (moDCs), and myeloid-derived suppressor cells (MDSCs). Postresolution mononuclear phagocytes were observed alongside lymph node expansion and increased numbers of blood and peritoneal memory T and B lymphocytes. The resMphis and moMphis triggered FoxP3 expression within CD4 cells, whereas moDCs drive T-cell proliferation. The resMphis preferentially clear apoptotic PMNs and migrate to lymph nodes to bring about their contraction in an inducible nitric oxide synthase-dependent manner. Finally, moMphis remain in tissues for months postresolution, alongside altered numbers of T cells collectively dictating the magnitude of subsequent acute inflammatory reactions. These data challenge the prevailing idea that resolution leads back to homeostasis and asserts that resolution acts as a bridge between innate and adaptive immunity, as well as tissue reprogramming.
Guilliams, M. et al., 2014.
Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny.
Nat Rev Immunol, 14, pp.571-8.
AbstractThe mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.