Damage-mediated macrophage polarization in sterile inflammation

Abstract

Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile inflammation, either as a cause or a consequence of these conditions. The ability to control the progression of inflammation toward tissue resolution before it becomes chronic holds significant clinical potential. During sterile inflammation, the initiation of inflammation occurs through damage-associated molecular patterns (DAMPs) in the absence of pathogen-associated molecules. Macrophages, which are primarily localized in the tissue, play a pivotal role in sensing DAMPs. Furthermore, macrophages can also detect and respond to resolution-associated molecular patterns (RAMPs) and specific pro-resolving mediators (SPMs) during sterile inflammation. Macrophages, being highly adaptable cells, are particularly influenced by changes in the microenvironment. In response to the tissue environment, monocytes, pro-inflammatory macrophages, and pro-resolution macrophages can modulate their differentiation state. Ultimately, DAMP and RAMP-primed macrophages, depending on the predominant subpopulation, regulate the balance between inflammatory and resolving processes. While sterile injury and pathogen-induced reactions may have distinct effects on macrophages, most studies have focused on macrophage responses induced by pathogens. In this review, which emphasizes available human data, we illustrate how macrophages sense these mediators by examining the expression of receptors for DAMPs, RAMPs, and SPMs. We also delve into the signaling pathways induced by DAMPs, RAMPs, and SPMs, which primarily contribute to the regulation of macrophage differentiation from a pro-inflammatory to a pro-resolution phenotype. Understanding the regulatory mechanisms behind the transition between macrophage subtypes can offer insights into manipulating the transition from inflammation to resolution in sterile inflammatory diseases.

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration

“…The question that these findings raised in the 1990s was how the activation of macrophages resulted in the development of atrophic and neovascular phenotypes, which were considered two very different processes at the time. The answer was slowly revealed over the next two decades with the discovery of different macrophage/microglial polarization states [117]. The potential for macrophages/microglia to polarize between a phagocytic proinflammatory and a vascular endothelial growth factor-producing angiogenic polarization state determine the development of geographic atrophy, exudative AMD, or both [59].…”

“…The classically activated (M1) and alternatively activated (M2) binary description of macrophage polarization, based on biomarker expression and cytokine production, does not reflect the true character of these subtypes. A function-based description of macrophage polarization better characterizes their role in pathology [59,117,118]. The M1 polarization state is characterized as the proinflammatory phagocytic state.…”

“…The M2 state can be subdivided into four M2 subtypes. The M2 a, b subtype are the anti-inflammatory profibrotic type, the M2d is the pro angiogenic phenotype, and the M2c is the anti-inflammatory and neuroprotective type [117][118][119]. The M2c can also dedifferentiate myofibroblasts, so is considered anti-fibrotic [120].…”

Omega-3 Lipid Mediators: Modulation of the M1/M2 Macrophage Phenotype and Its Protective Role in Chronic Liver Diseases

“…It is still necessary to understand the role of this SPM in the hepatocytes and how MaR1 connects the machinery related to the crosstalk among the most important type of cells in the liver (hepatocytes, KCs, HSCs, and others), not only to put an end to the damage in chronic liver diseases, but also to use it as a potential regenerative molecule. At present time, however, (i) the complex etiological factors for CLD and the large heterogeneity of KCs challenge the transfer of the current knowledge into the development of macrophage-targeted therapies for CLD; (ii) most of the previous studies on the roles and mechanisms of hepatic macrophages in CLD were carried out in rodent models, thus requiring future research into the applicability of these findings to humans; and (iii) considering that the precise functions and control mechanisms of liver macrophage subclasses in humans are limited, it is a major concern to just focus on the study of pathogenic phenotypes rather than the physiological and resolutive macrophages [115][116][117][118].…”

Macrophage polarization in infectious diseases: PAMP, viru-lence factors, immune signaling and receptors

“…During the innate immune response, the action of monocytes (MOs) and MOs differentiated into macrophages (MФs) has been reported as an important weapon of the human host against various pathogens. It has been extensively studied in the context of infections caused by viruses, protozoa, bacteria, and fungi [5][6][7][8]. These cells are involved in wound healing, the transition between innate and acquired immunity, and the maintenance of tissue homeostasis.…”