Chronic systemic inflammation (CSI) has recently been identified as a major contributor to common diseases ranging from cancer to metabolic disorders and neurologic alterations. In the last decade, we and others have generated genetically engineered mouse models for inflammatory diseases, which enable studying the molecular mechanisms of CSI. Recently, organ cross-talk induced by CSI under homeostatic and pathological conditions has begun to be appreciated. In this review, we will revisit whole organism physiology in relation to CSI originating from epithelial tissues, such as the skin and gut. Furthermore, we will discuss the current knowledge regarding the mechanisms, the specific immune cells and molecules responsible for inducing the most common comorbidities, such as cardiovascular, metabolic, and neurological complications, as well as bone loss, in heterogeneous diseases like psoriasis, atopic dermatitis, and inflammatory bowel disease. As it would be impossible to discuss all comorbidities of these diseases as well as all epithelial tissues, we present an overview with a special emphasis on our recent findings linking skin inflammation to bone loss.