Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy

Abstract

Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties

“…The release of soluble mediators by the tissue (including alarmins, cytokines and chemokines) leads to the local activation of collagen-producing mesenchymal cells, (the composition of ECM varies according to specific tissues [53]) and provides a distinctive cell microenvironment for the various tissue compartments [54]. As a result, local activation of fibroblasts, recruitment of fibroblast precursors, and the transition of various cell types into myofibroblasts lead to an excessive deposition of ECM, which replaces healthy parenchymal tissue with collagen-rich ECM components, thus resulting in a loss of the normal function of affected organs [55].…”