Differential Activation of Cell Death Pathways in Macrophages as a Result of Adaptation to Divergent Microenvironment

Macrophages are located throughout the body tissues, where they recognize, engulf and process foreign and endogenous microparticles, dead cells and debris, and produce specific information about the encountered objects. Macrophages are highly heterogeneous and can rapidly change their function and phenotype in response to local microenvironmental signals. Complex tissue ecosystems determine the polarization of macrophages so that they represent intermediate states in a whole spectrum of functions and phenotypes. Macrophages can die in several ways, and the inflammatory response to each form of cell death is highly variable. In contrast to the homeostatic and tolerogenic apoptosis, highly proinflammatory necrotic types of cell death, such as necroptosis and pyroptosis tend to trigger an immunogenic response. The immune consequence of another type of cell death, ferroptosis remains to be determined. Results obtained by single-cell analysis, that is increasingly being used to study macrophages, suggest that the cell death machinery is differentially expressed and activated within different microenvironments. Consequently, macrophages’ death appears to be an important component of their protective and pathogenic functions.

This Research Topic is based on two assumptions coming from the current state of macrophage biology: (i) exposure of macrophages to microenvironmental cues determines their ability to enter particular cell death pathways; (ii) death of macrophages is a newly recognized effector mechanism of innate immune response to microenvironmental challenge.

The coexistence of different cell death pathways in macrophages and their mutual regulation with surrounding tissues have not been extensively studied so far. Recent data suggest a gradual, multi-stage adaptation of the cell death machinery to the tissue microenvironment. The cell death preference of macrophages plays a critical role in immune responses. In human pathologies (e.g. tumors, cardiometabolic diseases, infectious diseases), distinct macrophage states can be associated with unfavorable or favorable clinical outcomes. The different macrophage states are not clearly defined by transcriptional signatures, but rather characterized by overlapping gene signatures. On the other hand, based on classical immunophenotyping, it is difficult to detect the differential predilection of macrophages to a particular cell death pathway. Here, we would like to discuss if macrophage death-linked signatures can be correlated with elements of their tissue microenvironment, and whether these signatures have potential diagnostic/prognostic value in human pathologies.

In this Research Topic, we welcome the submission of Original Research, Opinion, Review, and Mini Review articles focused on:
- Key factors driving changes in the cell death machinery of tumor-associated macrophages (TAMs) during their adaptation to the solid tumor microenvironment, including adaptation to the hypoxic and necrotic core, to tumor secreted lipids as well as to their immunosuppressive microenvironment;
- The regulation of cell death pathways in antitumor or tumor supporting macrophages (TAMs) as a result of interaction with other immune cells in the tumor site;
- Key factors driving changes in the cell death machinery of macrophages (and/or foam cells) present in atherosclerotic plaques during their adaptation to the plaque environment, including hypoxia, oxidative stress, oxidized lipids and interaction with other immune cells, e.g. neutrophils;
- Phenotypes and signatures of macrophages which adapt to the sustained presence of cytokines, PAMPs or/and DAMPs in different tissues;
- Therapeutic strategies targeting the microenvironment aimed at reprogramming the phenotype/function of macrophages as well as their cell death machinery during the progression of diseases;

Topic editor Philippe Saas is the author of a patent and a shareholder of the company Med’Inn’Pharma. All other Topic Editors declare no competing interests with regards to the Research Topic subject.