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Debra A Tokarz, Jeffrey A Yoder, Trim9 mediates macrophage chemotaxis in a RING-dependent manner, The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 202.24, https://doi.org/10.4049/jimmunol.196.Supp.202.24
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Abstract
Tissue infiltration by macrophages and neutrophils is an early and critical step in the innate immune response, yet excessive infiltration by these leukocytes can contribute to disease pathology. Defining intracellular mediators of neutrophil and macrophage chemotaxis will reveal novel targets for modulating inflammation. The tripartite motif (Trim) proteins are a family of E3 ubiquitin ligases, of which several members have defined roles in innate immune responses. Although previously considered to be brain-specific, we have identified trim9 as a gene with increased transcript levels within macrophages and neutrophils of larval zebrafish and of humans following immune stimulation with multiple toll-like receptor agonists. Prior to our studies, Trim9 had no reported immune function, however, its published role in control of axon growth guidance suggests it is important in cell migration. To investigate the role of Trim9 in leukocyte chemotaxis, we disrupted Trim9 function in zebrafish macrophages through expression of a truncated form of Trim9 that lacks the RING domain required for ubiquitin ligase activity (ΔRING-Trim9). Expression of ΔRING-Trim9 results in significantly reduced in vivo chemotaxis of zebrafish macrophages, while overexpression of full-length Trim9 under the same conditions does not. Further, macrophages expressing ΔRING-Trim9 exhibit altered morphology with reduced pseudopod formation. We propose that Trim9, through its ubiquitin ligase activity, may mediate cytoskeletal dynamics necessary for macrophage chemotaxis. Identifying Trim9 substrates and binding partners within macrophages may provide new therapeutic strategies for modulating inflammation.
