Macrophage migration inhibitory factor facilitates prostaglandin E2 production of astrocytes to tune inflammatory milieu following spinal cord injury

Abstract

Background Astrocytes have been shown to produce several pro- and anti-inflammatory cytokines to maintain homeostasis of microenvironment in response to vast array of CNS insults. Some inflammation-related cytokines are responsible for regulating such cell events. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that can be inducibly expressed in the lesioned spinal cord. Unknown is whether MIF can facilitate the production of immunosuppressive factors from astrocytes to tune milieu following spinal cord injury. Methods Following establishment of contusion SCI rat model, correlation of PGE 2 synthesis-related protein levels with that of MIF was assayed by Western blot. ELISA assay was used to detect production of PGE 2 , TNF-α, IL-1β, and IL-6. Immunohistochemistry was performed to observe colocalization of COX2 with GFAP- and S100β-positive astrocytes. The primary astrocytes were treated by various inhibitors to validate relevant signal pathway. Results The protein levels of MIF and COX2, but not of COX1, synchronously increased following spinal cord injury. Treatment of MIF inhibitor 4-IPP to the lesion sites significantly reduced the expression of COX2, mPGES-1, and as a consequence, the production of PGE 2 . Astrocytes responded robustly to the MIF interference, by which regulated MAPK/COX2/PGE 2 signal pathway through coupling with the CD74 membrane receptor. MIF-induced production of PGE 2 from astrocytes was able to suppress production of TNF-α, but boosted production of IL-1β and IL-6 in LPS-activated macrophages. Conclusion Collectively, these results reveal a novel function of MIF-mediated astrocytes, which fine-tune inflammatory microenvironment to maintain homeostasis. These suggest an alternative therapeutic strategy for CNS inflammation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1468-6) contains supplementary material, which is available to authorized users.

Dexamethasone induces aberrant macrophage immune function and apoptosis

“…While this implies that the microenvironment may change, which would support tumor growth due to prostaglandin production by COX-2 enzymatic activity, other mechanisms are possible. Decreased levels of COX-2 are relative to the abnormal immune function of macrophages (17,18). In the present study, it was revealed that KLF9, a direct target of GCs, could reduce LPS-induced COX-2 levels, indicating that KLF9 is a potent inhibitor of immune function in macrophages.…”

“…Inhibition of COX-2 may suppress the development of epithelial cell malignancies in the gastrointestinal tract (12)(13)(14). In addition, COX-2 has been revealed to modulate the fate of colon cancer cell lines by generating prostanoids (15)(16)(17). These observations indicate that COX-2 expression and prostanoid generation may play a fundamental role in the initiation and promotion of cancers arising from inflamed tissues, such as cholangiocarcinoma (18).…”

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

“…After SCI, reactive astrocytes, microglia and peripheral immune cells release proinflammatory cytokines and interact with each other, which contributes to the inflammation in the acute and subacute stage (Escartin et al, 2019). Reactive astrocytes also have negative feedback regulation for inflammation after SCI (Haan et al, 2015;Zhang et al, 2019). In summary, the glial scar and reactive astrocytes are not mere limiters of the inflammation but rather balancers which are not only limiting but also contributing to the inflammation.…”

Macrophage Migration Inhibitory Factor Promotes Inflammation in Human Dental Pulp

“…MIF stimulation also increased PTGS2 mRNA expression and PGE 2 secretion in microglial cells 29) . Furthermore, MIF was found to promote PGE 2 production from astrocytes after spinal cord injury 30) . These reports collectively suggest that MIF acts as an inflammatory cytokine that initiates the arachidonic acid cascade, thereby being involved in the regulation of the inflammatory environment.…”