Corticotropin-releasing hormone enhances the responsivity of macrophages to inflammation in zebrafish

The immunomodulatory role of steroid stress hormones, such as cortisol, are well characterized; however, less is known about how other stress hormones affect the immune system. Release of central corticotropin-releasing hormone (Crh) will result in an indirect anti-inflammatory effect due to the stimulation of cortisol production. Conversely, peripheral release of Crh is thought to directly exhibit proinflammatory effects on leukocytes. This suggests that the peripheral Crh system promotes inflammation, rather than suppresses it, but the molecular mechanisms are not well defined. To test the hypothesis that Crh will stimulate immune function, we used the zebrafish animal model and assessed leukocyte migration towards a wound as a readout of inflammatory capacity. We show that not only is crhr1 regulated during inflammation, but that it directly modulates the leukocyte population localized to a wound site. In particular, it enhances pro-inflammatory macrophage recruitment through the Cxcr3.2/Cxcr11aa signalling axis. Taken together, this work further contributes to our understanding of how Crh, and stress as a whole, can impact immune system function.