Glucocorticoids Shape Macrophage Phenotype for Tissue Repair

Abstract

Inflammation is a complex process which is highly conserved among species. Inflammation occurs in response to injury, infection, and cancer, as an allostatic mechanism to return the tissue and to return the organism back to health and homeostasis. Excessive, or chronic inflammation is associated with numerous diseases, and thus strategies to combat run-away inflammation is required. Anti-inflammatory drugs were therefore developed to switch inflammation off. However, the inflammatory response may be beneficial for the organism, in particular in the case of sterile tissue injury. The inflammatory response can be divided into several parts. The first step is the mounting of the inflammatory reaction itself, characterized by the presence of pro-inflammatory cytokines, and the infiltration of immune cells into the injured area. The second step is the resolution phase, where immune cells move toward an anti-inflammatory phenotype and decrease the secretion of pro-inflammatory cytokines. The last stage of inflammation is the regeneration process, where the tissue is rebuilt. Innate immune cells are major actors in the inflammatory response, of which, macrophages play an important role. Macrophages are highly sensitive to a large number of environmental stimuli, and can adapt their phenotype and function on demand. This change in phenotype in response to the environment allow macrophages to be involved in all steps of inflammation, from the first mounting of the pro-inflammatory response to the post-damage tissue repair.

The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration

“…(27,29,35,67,82)), we demonstrate that inflammation and MΦs/µglia are required for RPE regeneration in vivo. Synthetic GCs, such as dexamethasone, have been widely used to suppress inflammation and do so by attenuating the inflammatory phase post-injury and driving macrophages toward an anti-inflammatory phenotype (87)(88)(89). Results from our study support the existence of a critical inflammatory phase during RPE regeneration, as evidenced by expression of phagocytic (e.g.…”

“…Several phases have been characterized following tissue injury: I) the inflammatory phase, in which leukocytes are recruited, secrete pro-inflammatory cytokines, and begin phagocytosis; II) the resolution phase, in which macrophages continue to phagocytose cell debris and make the switch from a pro-to an anti-inflammatory phenotype; and III) the regeneration phase, in which injured tissues initiate proliferation (82,87). Indeed, sequential progression of resolution and regeneration phases have been shown post-tail fin resection in zebrafish (82).…”

“…GCs have been shown to have varying effects on macrophage migration (89); indeed, in GC-treated zebrafish post-wounding, leukocyte migration defects have been detected in some injury paradigms (27,35,67), but not others (90,91). Further, GCs have been shown to increase phagocytosis by macrophages to promote expedited resolution of inflammation (87,89), which may explain the lack of pyknotic nuclei accumulation in dexamethasone-treated larvae post-RPE damage. Collectively, the results from dexamethasone and irf8 mutant experiments hint at the existence of critical inflammatory and resolution phases post-RPE ablation, and we provide evidence that by-passing either phase results in the same outcome: impairment of RPE regeneration.…”

Glucocorticoids in Sepsis: To Be or Not to Be

“…It would be interesting to study whether GR Lysmcre mice are also sensitized in bacterial sepsis models such as the CLP model and, if so, whether this could be linked to an increased bacterial burden along with increased inflammation. Next to enhancing phagocytosis of bacteria, GCs also enhance the clearance of apoptotic cells and cell debris, i.e., efferocytosis, which is important to start tissue repair [see recent review on this topic; ( 56 )]. A possible mechanism explaining the apparently opposing effects of GCs in sepsis is by a GC-induced differentiation of a specific anti-inflammatory subtype of monocytes, which seems to be actively involved in resolution of inflammatory reactions instead of a global suppression of monocytic effector functions as was originally thought ( 57 ).…”

GILZ in sepsis: “Poor is the pupil who does not surpass his master”

“…Moreover, at low, physiological doses, GCs have been shown to dampen the systemic inflammatory response, while preserving innate immunity [11]. Several studies showed that dexamethasone, a typical GR ligand, increases the phagocytic activity of monocytes and macrophages using a variety of particles (zymosan, heat-killed yeast, apoptotic neutrophils, latex beads, bacteria) [13].…”