Abstract
The infiltration of immune cells into tissues underlies the establishment of tissue-resident macrophages and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here, we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio, which are themselves required for invasion. Both the filamin and the tetraspanin enhance the cortical activity of Rho1 and the formin Diaphanous and thus the assembly of cortical actin, which is a critical function since expressing a dominant active form of Diaphanous can rescue the Dfos macrophage invasion defect. In vivo imaging shows that Dfos enhances the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the properties of the macrophage nucleus from affecting tissue entry. We thus identify strengthening the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues.
Highlights
The classical model of cell migration on a surface postulated in the 1980s by Abercrombie has been extended [1] by studies showing that migrating cells utilize diverse strategies depending on the architecture and physical properties of their three-dimensional (3D) surroundings [2]
The transcription factor Dfos is required for macrophage germband invasion To identify regulators of programs for invasion, we searched the literature for transcription factors expressed in macrophages prior to or during their invasion of gb tissues (Fig 1A–1B’)
Blocking Dfos function in macrophages with a dominant negative (DN) Dfos (Fig 1O–Q) that lacks the activation domain but retains the capacity to dimerize and bind DNA [31] or 2 different RNA interferences (RNAis) against Dfos (Fig 1R) recapitulates the decrease in gb macrophages seen in the null while not affecting macrophage numbers in the whole embryo (S1C Fig) or along the ventral nerve cord (S1D and S1E Fig)
Summary
The classical model of cell migration on a surface postulated in the 1980s by Abercrombie has been extended [1] by studies showing that migrating cells utilize diverse strategies depending on the architecture and physical properties of their three-dimensional (3D) surroundings [2]. Most 3D migration occurs within the body, and much less research has elucidated the mechanisms used to efficiently move in these diverse environments, into and through tissues. Such migration is crucial for the influence of the immune system on health and disease. The mechanisms utilized by immune cells to allow migration into such challenging cellular environments in vivo are not well understood
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