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A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila.

ABSTRACT: Programmed cell death plays a fundamental role in development and tissue homeostasis. Professional and non-professional phagocytes achieve the proper recognition, uptake, and degradation of apoptotic cells, a process called efferocytosis. Failure in efferocytosis leads to autoimmune and neurodegenerative diseases. In Drosophila, two transmembrane proteins of the Nimrod family, Draper and SIMU, mediate the recognition and internalization of apoptotic corpses. Beyond this early step, little is known about how apoptotic cell degradation is regulated. Here, we study the function of a secreted member of the Nimrod family, NimB4, and reveal its crucial role in the clearance of apoptotic cells. We show that NimB4 is expressed by macrophages and glial cells, the two main types of phagocytes in Drosophila. Similar to draper mutants, NimB4 mutants accumulate apoptotic corpses during embryogenesis and in the larval brain. Our study points to the role of NimB4 in phagosome maturation, more specifically in the fusion between the phagosome and lysosomes. We propose that similar to bridging molecules, NimB4 binds to apoptotic corpses to engage a phagosome maturation program dedicated to efferocytosis.

SUBMITTER: Petrignani B

PROVIDER: S-EPMC8419693 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila.

Petrignani Bianca B Rommelaere Samuel S Hakim-Mishnaevski Ketty K Masson Florent F Ramond Elodie E Hilu-Dadia Reut R Poidevin Mickael M Kondo Shu S Kurant Estee E Lemaitre Bruno B

EMBO reports 20210809 9

Programmed cell death plays a fundamental role in development and tissue homeostasis. Professional and non-professional phagocytes achieve the proper recognition, uptake, and degradation of apoptotic cells, a process called efferocytosis. Failure in efferocytosis leads to autoimmune and neurodegenerative diseases. In Drosophila, two transmembrane proteins of the Nimrod family, Draper and SIMU, mediate the recognition and internalization of apoptotic corpses. Beyond this early step, little is kno ...[more]

PMID: 34370384

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Project description:Active elimination of apoptotic cells is very important for maintaining homeostasis of early embryos. Recent observations on mouse blastocysts freshly isolated from healthy dams have shown that the majority of incidentally occurring apoptotic cells is eliminated by neighbouring embryonic cells. Some apoptotic cells escape phagocytosis, but the frequency of such processes usually does not exceed 10%. The aim of the current study was to evaluate whether the non-professional embryonic phagocytes can respond to experimentally induced increase in apoptosis by increasing the frequency of efferocytosis and whether their activity can be decreased by selective inhibition of specific component of efferoctosis machinery. Experiments were performed in vitro on cultured mouse blastocysts with a differentiated trophectoderm and inner cell mass and on the human trophoblast cell line Ac-1M88. Samples were assessed using fluorescence immunostaining: Apoptotic cells (TUNEL) internalised within the cytoplasm of non-professional embryonic phagocytes (phalloidin T membrane staining) were considered ingested; apoptotic cells co-localised with acidified phagosomes (LysoTracker) were considered digested. First, we tested the ability of embryonic phagocytes to respond to elevated incidence of apoptosis induced by actinomycin D (4 nM). The results showed that the increase in apoptosis was accompanied by a significant elevation of the phagocytosis and digestion of dead cells in both mouse blastocysts and human trophoblast cells. We then assessed the effect of selective inhibition of lysosomal acidification in embryonic phagocytes using a specific V-ATPase inhibitor bafilomycin A1. The results showed that the inhibitor at 0.1 and 0.2 nM was able to negatively affect the execution of both initiative and terminal phases of efferocytosis in mouse blastocysts, although the decrease was not as profound as expected. When compared to mouse trophectoderm cells, human hybrid cells displayed a very low sensitivity to bafilomycin A1. Higher concentrations of bafilomycin A1 had a more harmful impact on overall cell viability than on digestive activity. The results show that the ability of non-professional embryonic phagocytes to successfully execute all stages of efferocytosis is not limited by the frequency of apoptosis and is preserved even at elevated rates of the apoptotic process. The effectiveness of embryonic phagocytes can be partially decreased by selective inhibition of lysosomal acidification conducted via V-ATPase.

Project description:Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.

Dataset Information

A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila.

Publications

A secreted factor NimrodB4 promotes the elimination of apoptotic corpses by phagocytes in Drosophila.

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