Regenerative inflammation: When immune cells help to re-build tissues.

Inflammation is an essential immune response critical for responding to infection, injury and maintenance of tissue homeostasis. Upon injury, regenerative inflammation promotes tissue repair by a timed and coordinated infiltration of diverse cell types and the secretion of growth factors, cytokines and lipids mediators. Remarkably, throughout evolution as well as mammalian development, this type of physiological inflammation is highly associated with immunosuppression. For instance, regenerative inflammation is the consequence of an in situ macrophage polarization resulting in a transition from pro-inflammatory to anti-inflammatory/pro-regenerative response. Immune cells are the first responders upon injury, infiltrating the damaged tissue and initiating a pro-inflammatory response depleting cell debris and necrotic cells. After phagocytosis, macrophages undergo multiple coordinated metabolic and transcriptional changes allowing the transition and dictating the initiation of the regenerative phase. Differences between a highly efficient, complete ad integrum tissue repair, such as, acute skeletal muscle injury, and insufficient regenerative inflammation, as the one developing in Duchenne Muscular Dystrophy (DMD), highlight the importance of a coordinated response orchestrated by immune cells. During regenerative inflammation, these cells interact with others and alter the niche, affecting the character of inflammation itself and, therefore, the progression of tissue repair. Comparing acute muscle injury and chronic inflammation in DMD, we review how the same cells and molecules in different numbers, concentration and timing contribute to very different outcomes. Thus, it is important to understand and identify the distinct functions and secreted molecules of macrophages, and potentially other immune cells, during tissue repair, and the contributors to the macrophage switch leveraging this knowledge in treating diseases.