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.
