Heme oxygenase-1 mediates cytoprotective effects of immunostimulation in microglia

Microglia are brain-resident immune cells playing a pivotal role in the neuroinflammation. Previously, it has been shown that immunostimulation protects microglial cells against nitric oxide toxicity. Herein, we report that heme oxygenase-1 (HO-1) mediates the protective effects of immunostimulation. Pro-inflammatory activation of BV-2 microglial cells with endotoxin lipopolysaccharide (LPS) conferred a protection against various cytotoxic stimuli, whereas anti-inflammatory cytokines such as IL-4 and IL-10 were without effects. The LPS-induced cytoprotection was accompanied by HO-1 induction. The cytoprotective effect of LPS treatment was significantly attenuated by co-treatment with a HO-1 inhibitor, zinc protoporphyrin. Adenoviral expression of HO-1 in microglial cells was similarly cytoprotective, indicating that HO-1 mediates the cytoprotective effects of pro-inflammatory stimulation. Additional experiments revealed the involvement of carbon monoxide (CO) and iron, products of HO-1-mediated heme degradation, in the cytoprotective effect of LPS. Taken together, our results suggest that immunostimulation of microglia with LPS provides cytoprotective effects via HO-1 induction followed by the generation of CO and iron.