Tissues Use Resident Dendritic Cells and Macrophages to Maintain Homeostasis and to Regain Homeostasis upon Tissue Injury: The Immunoregulatory Role of Changing Tissue Environments

Figure 4

Translating the paradigm of classically activated (M1) and alternatively activated (M2) macrophage into clinical contexts. Classically activated (M1) macrophages promote tissue inflammation and immunopathology based on their role in host defense against intracellular pathogens. Extracellular pathogens are mostly attached by humoral factors such as complement, but when they persist, alternatively activated (M2) macrophages provide means of host defence that involve anti-inflammatory, progenerative, and profibrotic elements. The balance of inflammation and fibrosis varies over time and is different in different disease states and often operates in parallel. For this reasons tissue biopsies often become difficult to read and display a mixture of all these elements. The figure provides examples of common disease entities to illustrate how changing tissue environments involve M1- and M2-macrophages-mediated pathology either in a sequential manner, in an intermittent manner, or in a parallel manner, which largely depends on the associated underlying disease processes and cofactors. We propose that the sequential pattern shown at the top was the one that dominated during the evolution of wound healing from the stage of the first multicellular organisms, for example, healing of mechanical trauma in nonsterile environments. We further propose that all other mixtures that doctors often get to see in pathology textbooks and in their clinics originate from that and represent maladaptive variants of this underlying danger response program that was otherwise extremely successful during evolution.