Extrinsic and intrinsic control of macrophage inflammatory responses

Abstract

Macrophages make major contributions to inflammatory immunopathology. In this work, we examine three disease scenarios, in which M1s play a major role early in the disease but eventually transitions into a population of cells with immunoregulatory activity. We propose that the transition from an inflammatory to a regulatory phenotype is a natural progression that regularly occurs in stimulated macrophages and that the timing of this transition is critical to maintaining homeostasis. In the first section of this review, we discuss the exogenous microenvironmental cues that may induce macrophages to enter a regulatory state. In the second half of this review, we discuss a novel mechanism, whereby TLR-stimulated macrophages can intrinsically induce their own regulatory activation state. They do so by secreting and synthesizing endogenous "reprogramming" signals that work in an autocrine fashion to promote a regulatory phenotype. We propose that these endogenous regulatory mechanisms exist to prevent macrophage-mediated immunopathology. Thus, macrophages can respond to endogenous and exogenous cues to regulate their activation state, and without these controlled regulatory responses, M1 would persist to the detriment of the host.

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…1,2 During the inflammatory response, tissue Mws are expected to sequentially develop into three different subpopulations: type-1 (Mw-1), type-2 (Mw-2) and regulatory (Reg-Mws). [3][4][5][6] During the initiation phase of inflammation, the pro-inflammatory Mw-1 subtype is generated in response to two signals (i.e., Interferon gamma (IFN-c) and tumor-necrosis factor alpha (TNF-a)) or a Toll-like receptor (TLR) ligand, such as lipopolysaccharide (LPS). During the resolution phase of inflammation, the presence of the type-2 cytokines interleukin 4 (IL-4) and IL-13 leads to the generation of anti-inflammatory Mw-2, which are associated with the coordination of tissue repair.…”

“…The third subtype (i.e., Reg-Mws) is fundamentally different from Mw-1 and Mw-2, and the generation of this subtype requires two signals. [3][4][5][6] The first signal may include IL-10, prostaglandins, immune complexes, adenine nucleotides, glucocorticoids and apoptotic cells, and the second signal is TLR activation. RegMws overproduce IL-10 but not IL-12 and exhibit potent immunosuppressive activity for modulating the acute inflammatory response and limiting tissue damage.…”

“…RegMws overproduce IL-10 but not IL-12 and exhibit potent immunosuppressive activity for modulating the acute inflammatory response and limiting tissue damage. [3][4][5][6] Tissue Mws constitute one of the most abundant populations of inflammatory cells in the uterus, and the numbers of these cells remain relatively constant in the decidua throughout gestation. 7,8 In normal pregnancies, the phenotype of uterine Mws is locally modified to acquire a type-2 phenotype, 9-11 which may contribute to trophoblast differentiation, support embryo implantation and supply growth factors to the placenta.…”

Activation of Macrophages <i>in vitro</i> by Phospholipids from Brain of <i>Katsuwonus pelamis</i> (Skipjack Tuna)

“…Macrophages make major contributions to respond to infection and enhance immune responses by secretion of myriad inflammatory cytokines and mediators, such as TNF-α, IL-1, lL-6, ROS and so on 24 . During inflammation, TNF-α exerts protective effects in early infection via inhibiting bacterial growth and macrophage death.…”

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

“…Macrophages are the most abundant innate immune cells distributed throughout the body and are implicated in various types of infections/inflammation and cancer (1)(2)(3)(4)(5). They also have the plasticity to quickly deal with endangering signals in the organs where they reside.…”