Toll-like receptor adaptor protein TIRAP has specialized roles in signaling, metabolic control and leukocyte migration upon wounding in zebrafish larvae

The TIRAP protein is an adaptor protein in TLR signaling which links TLR2 and TLR4 to the adaptor protein Myd88. The transcriptomic profiles of zebrafish larvae from a <i>tirap</i>, <i>myd88</i> and <i>tlr2</i> mutant and the corresponding wild type controls under unchallenged developmental conditions revealed a specific involvement of <i>tirap</i> in calcium homeostasis and myosin regulation. Metabolomic profiling showed that the <i>tirap</i> mutation results in lower glucose levels, whereas a <i>tlr2</i> mutation leads to higher glucose levels. A tail-wounding zebrafish larval model was used to identify the role of <i>tirap</i> in leukocyte migration to tissue wounding. We found that more neutrophils were recruited to the wounded region in the <i>tirap</i> mutant larvae compared to the wild type controls, whereas there was no difference in macrophage recruitment. In contrast, published data show that <i>tlr2</i> and <i>myd88</i> mutants recruit fewer neutrophils and macrophages to the wounds. Based on cell tracking analysis, we demonstrate that the neutrophil migration speed is increased in the <i>tirap</i> mutant in contrast to neutrophil behavior in <i>myd88</i> and <i>tlr2</i> mutants. In conclusion, we show that <i>tirap</i> plays specialized roles distinct from <i>tlr2</i> and <i>myd88</i> in signaling, metabolic control, and in regulating neutrophil migration speed upon wounding.