A soluble form of the CSF-1 receptor contributes to the inhibition of inflammation in a teleost fish

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★ We examine the impact of a novel teleost soluble cytokine receptor on inflammation. ★ This soluble CSF-1R plays a role beyond the control of macrophage proliferation. ★ In vitro and in vivo approaches are used to characterize sCSF-1R activity. ★ ROS production and leukocyte infiltration are inhibited by sCSF-1R. ★ We provide new insights into evolutionary origins of CSF-1 immune regulatory axis.

We previously reported on the identification of a novel soluble form of the CSF-1 receptor (sCSF-1R) in goldfish that induced dose-dependent down-regulation of macrophage proliferation. Herein, we report that sCSF-1R has a role beyond macrophage development, which extends into the control of cellular antimicrobial inflammatory responses in this lower vertebrate. Using an in vivo model of self-resolving peritonitis coupled to in vitro characterization of sCSF-1R activity, we show that sCSF-1R plays a role in the inhibition of inflammation which follows an initial acute phase of innate antimicrobial responses within an inflammatory site. In vitro, mature goldfish primary kidney macrophages but not monocytes up-regulated sCSF-1R expression upon direct contact with apoptotic cells. In vivo, sCSF-1R expression coincided with an increase in macrophage numbers that resulted from administration of apoptotic cells into the goldfish peritoneal cavity. This contrasted the decrease in sCSF-1R expression during zymosan-induced inflammatory responses in vivo. Subsequent experiments showed an anti-inflammatory effect for sCSF-1R. Leukocyte infiltration and ROS production decreased in a dose-dependent manner compared to zymosan-stimulated controls upon addition of increasing doses of recombinant sCSF-1R. Among others, sCSF-1R may contribute to the dual role that phagocytic macrophages play in the induction and regulation of inflammation. Overall, our results provide new insights into ancient mechanisms of inflammation control and, in particular, the evolutionary origins of the CSF-1 immune regulatory axis.

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