Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis

Abstract

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and an-tiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more anti-inflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair.

Fig. 1

Tissue microenvironments and predominant macrophage phenotypes. Acute tissue injury induces cell necrosis, hence the local microenvironment will be dominated by DAMPs. In nonsterile organs or during infections, PAMPs add to a tissue environment rich in factors that ligate pattern recognition receptors and drive macrophage polarization towards the M1-like proinflammatory phenotype. After the inflammatory response has cleared the sources of PAMPs and DAMPs, pentraxins and apoptotic cells, e.g. neutrophils, dominate the tissue environment which promotes macrophage polarization towards an anti-inflammatory M2-like phenotype that produces anti-inflammatory mediators which enrich the anti-inflammatory and proregenerative tissue environment. Once inflammation has completely ceased, the microenvironment is dominated by growth factors that promote wound healing, especially in conditions of incomplete or insufficient epithelial repair. This environment drives macrophage polarization towards a profibrotic phenotype that contributes to the secretion of additional growth factors as well as ECM components. The ischemic environment of scar tissue is largely devoid of cytokine and growth factors which drives the few macrophages in place to predominately secrete proteases that have the potential to remove connective tissue, i.e. the fibrolytic macrophages. In vivo all four types of macrophages can coexist in different areas of the same organ with focal lesions of active inflammation, early and late repair, as well as scar formation. This needs to be considered while characterizing macrophage phenotypes from tissue biopsies.