Myeloid lineage plasticity in response to inflammatory signals

The mononuclear phagocytic system exerts important functions in tissue homeostasis and host defense. MPS family members including monocytes, tissue macrophages and dendritic cells are regenerated from precursors throughout life. Most members of the MPS system are replenished from a blood-derived monocytes or monocyte/dendritic cell committed precursor cell stage that in turn arises from granulocyte/monocyte progenitors (GMPs). Neutrophil granulopoiesis and monocyte/dendritic cell development are regarded as two separate progenitor cell differentiation pathways originating from GMPs. Several critical transcription factors regulate differential commitment to either pathway. Furthermore, granulocyte development proceeds through well-defined intermediate cell stages. Mitogen-activated protein kinase (MAPK) kinase MKK6 is a direct and selective upstream kinase of p38MAPK. Our preliminary data show that the selective conditional activation of the MKK6-p38 signalling cascade in late-stage granulocytes induces their "transdifferentiation" towards CD14hi monocyte-like cells. Moreover, this effect is duplicated when stimulating late stage Lactoferrin (LF)+ granulocytes with a combination of pro-inflammatory cytokines which strongly activate the MKK6/P38 pathway. Moreover, CD14hi cells arising from neutrophils could be induced to further differentiate to osteoclasts, consistent with MKK6 dependency of this lineage. Interestingly, constitutively phosphorylated MKK6 marks monocytes/macrophages and synoviocytes in inflammatory arthritis lesions and p-p38 is expressed at elevated levels in certain myelodysplastic syndrome (MDS) cases associated with altered granulocyte and monocyte differentiation. Comparatively little is known on the consequences of sustained MKK6/p38 activation on myeloid cells. Here we ask: (1) What are the downstream mechanisms underlying MKK6-induced inhibition of granulocytes and transdifferentiation to CD14hi monocyte-like cells? (2) Is sustained activation of MKK6-p38 associated with neutropenia and monocyte differentiation in pathophysiologic conditions?

The Mononuclear Phagocytic System (MPS) represents an important component of the human immune system, fulfilling tasks in tissue homeostasis (elimination of "old" autologous cell material) and resistance to pathogens. The MPS consists of monocytes, tissue macrophages and dendritic cells and is regenerated throughout life by hematopoiesis (development / differentiation of blood cells). Neutrophils and cells of the MPS conduct different functions and tasks in the immune system and arise from a common precursor cell (granulocyte-monocyte precursor cell; GMP) by separate differentiation pathways. The general assumption is that after differentiation into mature neutrophils or monocytes, the mature cells lose their potential to differentiate into other cell types of the hematopoietic system. However, recent research results suggested that mature neutrophils may transdifferentiate into monocytes. "Transdifferentiation" refers to the "conversion" of a mature cell into another cell type that has a completely different morphology and function. The transdifferentiation process shows that the assumption a mature cell were bound to its morphology and function, should be reconsidered. The transdifferentiation process seems to have a role in the development and pathogenesis of various acute or chronic inflammatory diseases. The triggering mechanisms that initiate transdifferentiation of neutrophils to monocytes were unknown. Our hypothesis was that the transdifferentiation of neutrophils occurs in an inflammatory milieu. Our work shows that the activation of the MKK6 - p38 signalling pathway by inflammatory cytokines initiates the conversion of neutrophils to monocytes. Detailed studies of the process of conversion showed that the expression of important transcription factors is down regulated in neutrophils, while monocyte-determining transcription factors are up regulated. In summary, this work describes for the first time a pathway activated by inflammatory cytokines (MKK6 - p38) which triggers the conversion of neutrophils in monocytes with subsequent changes in the expression of monocyte- determining transcription factors. In addition, further experiments in mouse models have shown that a transdifferentiation process of neutrophils in inflammatory lesions, such as in the peritonitis or rheumatoid arthritis, occurs. Understanding the basic mechanisms and pathways triggering the transdifferentiation process is important to selectively block this process, which may lead to positive effects in the pathogenesis of chronic inflammation.