15 research outputs found

    MafB-restricted local monocyte proliferation precedes lung interstitial macrophage differentiation.

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    peer reviewedResident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C+ classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206+ IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo

    Lung Interstitial Macrophages: Past, Present, and Future

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    For a long time, investigations about the lung myeloid compartment have been mainly limited to the macrophages located within the airways, that is, the well-known alveolar macrophages specialized in recycling of surfactant molecules and removal of debris. However, a growing number of reports have highlighted the complexity of the lung myeloid compartment, which also encompass different subsets of dendritic cells, tissue monocytes, and nonalveolar macrophages, called interstitial macrophages (IM). Recent evidence supports that, in mice, IM perform important immune functions, including the maintenance of lung homeostasis and prevention of immune-mediated allergic airway inflammation. In this article, we describe lung IM from a historical perspective and we review current knowledge on their characteristics, ontogeny, and functions, mostly in rodents. Finally, we emphasize some important future challenges for the field

    Rab guanine nucleotide exchange factor 1 (Rabgef1) restricts intestinal inflammation by limiting pro-inflammatory signals in Intestinal Epithelial Cells (IECs)

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    Rab guanine nucleotide exchange factor (GEF-)1 (Rabgef1), a multifunctional protein whose in vivo functions remained unknown until recently, is highly expressed in mouse and human epithelial cells. The aim of this study is to investigate the role of Rabgef1 in intestinal epithelial cells (IECs) and intestinal homeostasis in mice. We performed conditional deletion of Rabgef1 gene using the cre-lox system to obtain mice lacking Rabgef1 specifically in IECs (Rabgef1IEC-KO), under the wild-type (WT) or the colitis-prone Interleukin-10 (Il-10)-deficient background. In addition, we used the CRISPR-Cas9 technology to obtain a murine IEC line deficient in Rabgef1. Rabgef1IEC-KO mice under the WT background did not develop spontaneous intestinal abnormalities but exhibited an altered intestinal microbial composition associated with minor changes in IEC pro-inflammatory gene expression profile. Moreover, Rabgef1IEC-KO mice exhibited an increased susceptibility to inflammation in a dextran sodium sulfate (DSS)-induced model of colitis under the WT background, as well as in a constitutive model of colitis under the Il-10-¬deficient background. In vitro, we showed that mouse IECs lacking Rabgef1 significantly overexpressed several pro-inflammatory cytokines and chemokines as compared to control cells. Taken together, these results support that Rabgef1 acts as a regulator of intestinal homeostasis and inflammation, and that dysregulated Rabgef1 expression could contribute to intestinal barrier dysfunction in inflammatory conditions of the gut

    Epithelial Rab guanine nucleotide exchange factor 1 (Rabgef1) deficiency increases susceptibility to DSS-induced intestinal inflammation in mice

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    Rab guanine nucleotide exchange factor (GEF)1 (Rabgef1) is a guanine nucleotide exchange factor for the endocytic GTPase Rab5, and also exhibits E3 ubiquitin ligase activity in vitro. In vivo functions of Rabgef1 remain largely unknown, but Rabgef1 is critical for health, as globally Rabgef1-deficient mice exhibit perinatal mortality and those surviving to adulthood spontaneously develop severe skin inflammation.This protein is highly expressed in murine intestinal epithelial cells (IECs). Objective: The aim of this study is to clarify the role of Rabgef1 in murine IECs Materials and methods: We performed conditional deletion of Rabgef1 using the cre-lox system to obtain mice lacking Rabgef1 specifically in IECs (Rabgef1IEC-KO). Results: Rabgef1IEC-KO mice did not develop spontaneous intestinal abnormalities but showed an increased susceptibility to inflammation in dextran sodium sulfate (DSS)-induced col itis model. Indeed, compared to littermate controls, mice lacking Rabgef1 in IECs exhibited shorter and highly inflamed colons and higher inflammatory scores in histopathological examination of colons, suggesting that Rabgef1 expression regulates IEC function and is critical in limiting DSS induced inflammation and damage. In addition, we also showed that mRNA expression of pro-inflammatory cytokines, such as Il1b and Tnfa, was upregulated in IECs isolated from Rabgef1IEC-KO mice compared to the ones isolated from littermate controls. Conclusion: Taken together, these results suggest that Rabgef1 acts as a regulator of intestinal homeostasis, and that dysregulated Rabgef1 expression could contribute to intestinal barrier dysfunction in inflammatory conditions of the gut
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