The nervous and the immune system coevolved, and the crosstalk between both is critical for the maintenance of tissue homeostasis and mental health. In recent years, several examples have been revealed that the immune system influences behaviour, emotions, pain and even such fundamental needs as hunger. Reciprocally, several examples have become apparent in which neuronal innervation regulates local immune responses, wound healing and immune-mediated tissue homeostasis. Such findings demonstrate how well these two networks are interconnected with each other to sustain the body’s well-being. Nonetheless, the underlying mechanisms that orchestrate this interconnection remain poorly understood. The Epidermal Growth Factor Receptor (EGFR) signalling pathway exemplifies this connection, being involved in both neuronal development and maintenance as well as in immune regulation and immune mediated wound healing. Particularly two antagonistic and leukocyte-derived EGF-like growth factors, Amphiregulin and HB-EGF, have gained appreciation for their role in the regulation of local immune responses and the maintenance of tissue homeostasis. In this review, we highlight the role of these two leukocyte-derived growth factors in the regulation of the nervous system and their importance in the bi-directional crosstalk between the immune and nervous systems during tissue homeostasis and inflammation. Ultimately, we propose that under inflammatory conditions, these two leukocyte-derived growth factors may substitute typical neurotrophic factors in their function.