Review: Following the smoke signals: inflammatory signaling in metabolic homeostasis and homeorhesis in dairy cattle.

Inflammatory cascades are a critical component of the immune response to infection or tissue damage, involving an array of signals, including water-soluble metabolites, lipid mediators and several classes of proteins. Early investigation of these signaling pathways focused largely on immune cells and acute disease models. However, more recent findings have highlighted critical roles of both immune cells and inflammatory mediators on tissue remodeling and metabolic homeostasis in healthy animals. In dairy cattle, inflammatory signals in various tissues and in circulation change rapidly and dramatically, starting just prior to and at the onset of lactation. Furthermore, several observations in healthy cows point to homeostatic control of inflammatory tone, which we define as a regulatory process to balance immune tolerance with activation to keep downstream effects under control. Recent evidence suggests that peripartum inflammatory changes influence whole-body nutrient flux of dairy cows over the course of days and months. Inflammatory mediators can suppress appetite, even at levels that do not induce acute responses (e.g. fever), thereby decreasing nutrient availability. On the other hand, inhibition of inflammatory signaling with non-steroidal anti-inflammatory drug (NSAID) treatment suppresses hepatic gluconeogenesis, leading to hypoglycemia in some cases. Over the long term, though, peripartum NSAID treatment substantially increases peak and whole-lactation milk synthesis by multiparous cows. Inflammatory regulation of nutrient flux may provide a homeorhetic mechanism to aid cows in adapting to rapid changes in metabolic demand at the onset of lactation, but excessive systemic inflammation has negative effects on metabolic homeostasis through inhibition of appetite and promotion of immune cell activity. Thus, in this review, we provide perspectives on the overlapping regulation of immune responses and metabolism by inflammatory mediators, which may provide a mechanistic underpinning for links between infectious and metabolic diseases in transition dairy cows. Moreover, we point to novel approaches to the management of this challenging phase of the production cycle.