Neurons and astroglia govern microglial endotoxin tolerance through macrophage colony-stimulating factor receptor-mediated ERK1/2 signals

Abstract

Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor α, nitric oxide, prostaglandin E2 and interleukin 1β). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages.

Chronic pain and impaired glial glutamate transporter function in lupus‐prone mice are ameliorated by blocking macrophage colony‐stimulating factor‐1 receptors

“…Previous studies showed that microglial activation and proliferation are regulated by CSF‐1 (Chu et al . ; Guan et al . ; Okubo et al .…”

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

“…Upon activation, CSF1R associates with several signaling molecules, notably phosphoinositide 3-kinase (PI3K) [58]. CSF1R also activates Akt [11], and it induces ERK1/2-mediated signaling in microglia [9]. Akt [22,67] and ERK1/2 [19] are involved in the phagocytic process.…”

Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down‐modulating PGE2 production

“…6,9,46 Fewer reports exist in relation to the central mechanisms of endotoxin tolerance, even though this topic has been aptly addressed in important recent studies in the literature. 47,48 Besides, in an elegant experiment described by Chu et al 49 while neurons and astroglia are affected by chronic neuroinflammation, microglia fails to develop endotoxin tolerance. The authors concluded that the absence of microglial endotoxin tolerance could be important for the pathogenetic mechanisms involved in inflammation-associated neuronal damage.…”