Following acute CNS injury, CNS elicits a coordinated multicellular inflammatory response that involves glia, neurons, as well as various immune cells [
15]. The interaction between these cells constitutes a complex regulatory network of inflammation. For instance, the resident microglia and infiltrating immune cells have been implicated in driving astrocyte-mediated inflammation, while cytokine-stimulated astrocytes also induce migration of immune cells toward lesion sites [
42,
43]. It is interesting to note that injured CNS has potential to maximize the preservation of healthy tissue and restricting the spread of cytotoxic inflammation [
44]. Astrocytes, the important modulator of milieu, are able to provide benefits to the CNS by phagocytosis of synapses, secretion of neurotrophins, clearance of debris, repair of the BBB, as well as formation of a scar to enclose the necrotic lesion and restrict cytotoxic inflammation [
45]. Recently, the metabolites of arachidonic acid lipoxins A4 and B4 have been found to be secreted by astrocytes to promote neuroprotection from acute and chronic injury [
46]. In the present study, we have presented that astrocyte-derived PGE
2 is able to change the components of inflammatory microenvironment, suggesting the dynamic effects of astrocytes on inflammatory homeostasis following SCI.
MIF is constitutively expressed in a variety of immune and non-immune cells of different histogenetic origin. It shows a remarkable functional diversity ranging from activating the production of inflammatory cytokines including TNF-α, IL-1β, IL-6, and IFN-γ to inhibiting p53-mediated cell apoptosis [
47]. Given such broad activities, it is not surprising that this pluripotent and pleiotropic cytokine is implicated in acute and chronic inflammatory diseases such as rheumatoid arthritis, asthma, diabetes, sepsis, cardiovascular diseases, and cancer [
47‐
49]. During progression of cancer, MIF has the ability to change tumor microenvironment favorable for tumor aggressiveness. MIF promotes alternative macrophage differentiation that lead to formation of tumor-associated macrophages (TAMs). These TAMs are abundant in the tumor environment and act roles of immunosuppression [
50]. In the central nervous system, MIF is inducibly expressed in neurons within the hypothalamus, cortex, and hippocampus to modulate nitric oxide production as well as catecholamine metabolism [
51]. Also, it induces neuronal death after compression-induced spinal cord injury [
29]. We have shown that MIF is capable of promoting release of chemokine CCL5 from astrocytes, which in turn primarily promote migration of M2-macrophages. In the present study, we displayed that MIF could induce PGE
2 release from astrocytes to change production of inflammatory cytokines, suggesting multiple mechanisms of MIF in modulation of inflammatory microenvironment following SCI.
PGE
2 has been found to play a wide range of roles in acute and chronic injury of CNS [
52], such as contributing to excitotoxic and ischemic neuronal cell death [
53], or neuronal protection [
54,
55], depending on its interacting receptor(s). With respect to its function in modulating inflammation in the context of pathophysiological conditions, PGE
2 has been demonstrated to exert both proinflammatory and immunodepressive actions. During the acute stage of the inflammatory response, PGE
2 acts as a vasodilator and facilitates tissue infiltration of neutrophils [
56], macrophages [
57], as well as being a regulator of nociception [
58]. However, mounting evidence has also shown that PGE
2 modulates macrophage activation in part by suppressing the release of cytokines and/or chemokines. For example, PGE
2 is a negative regulator for LPS-induced production of TNF-α in Epac/PKA-, of IFN-β in Epac/PI3K/Akt-dependent signaling in activated macrophages and during endotoxemia [
40,
41]. Within the dying cells, PGE
2 is induced and released to function as an inhibitory DAMP for inhibiting the expression of genes associated with inflammation, thereby limiting the cell’s immunostimulatory activities [
59]. It is noteworthy that PGE
2 plays an opposing role on IL-1β production from monocytes/macrophages. In primary human monocytes, PGE
2 boosted LPS-induced IL-1β production [
60]. While in human macrophages, PGE
2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cAMP, leading to reduction in IL-1β secretion [
61]. In the present study, we displayed that PGE
2 attenuated LPS-induced TNF-α, but promoted IL-1β and IL-6 production in macrophage RAW 264.7 cells, suggesting its cell-specific influence on the production of inflammatory cytokines. Although PGE
2-mediated effects have been found to associate with the resolution of acute inflammation [
24], facilitation of tissue regeneration [
62], or aggravation of the disease phenotype such as chronic inflammation or cancer [
63], its contribution in the injured cord by altering the production of proinflammatory cytokines from macrophages deserves further study. Because reactive astrocytes have potential roles on promoting and restricting inflammation following CNS injury [
45], PGE
2-released by astrocytes might play a role in tuning the microenvironment to maintain homeostasis following SCI.