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JAK1/2 Regulates Synergy Between Interferon Gamma and Lipopolysaccharides in Microglia
Alexander P Young1, Eileen M Denovan-Wright2
1Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. alex.young@dal.ca.
Abstract:
Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.
Insights
Lipopolysaccharide (LPS) and interferon gamma (IFNγ) synergistically activate brain immune cells (microglia), leading to neuroinflammation. JAK1/2 inhibition effectively prevents this harmful microglial response.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Cellular Signaling
Background:
- Microglia are brain immune cells that regulate neuroinflammation, crucial for preventing neuronal damage and cognitive decline.
- Lipopolysaccharide (LPS) from gram-negative bacteria and interferon gamma (IFNγ) are potent stimulators of microglial inflammatory responses.
- Understanding the interplay between LPS and IFNγ is vital for developing treatments for pathological conditions involving neuroinflammation.
Purpose of the Study:
- To investigate the concentration-dependent synergistic effects of LPS and IFNγ on microglial and macrophage inflammatory activity.
- To identify the specific signaling pathways mediating the synergistic pro-inflammatory response induced by LPS and IFNγ.
- To evaluate the efficacy of JAK1/2 inhibition in preventing LPS- and IFNγ-induced microglial hyperactivation.
Main Methods:
- Cultured microglia and macrophages were treated with varying concentrations of LPS from different bacterial species and IFNγ.
- Pro-inflammatory activity was measured, and signaling pathways were analyzed using a panel of inhibitors.
- The effect of ruxolitinib, a JAK1/2 inhibitor, was assessed on LPS- and IFNγ-induced responses.
Main Results:
- LPS and IFNγ exhibited synergy in inducing a pro-inflammatory microglial phenotype, which was completely abrogated by JAK1/2 inhibition.
- The synergistic response was dependent on JNK and Akt signaling pathways, not solely on canonical NF-κB activation.
- LPS from different bacteria (E. coli, K. pneumoniae, A. muciniphila) elicited distinct inflammatory profiles, but ruxolitinib consistently prevented these responses.
Conclusions:
- A synergistic mechanism exists between LPS and IFNγ that leads to microglial hyperactivation, mediated by JAK1/2, JNK, and Akt signaling.
- JAK1/2 inhibition, specifically with ruxolitinib, offers a consistent therapeutic strategy to suppress LPS- and IFNγ-driven neuroinflammation.
- This study elucidates a critical molecular pathway for microglial activation, relevant to diverse pathological conditions with elevated LPS and IFNγ.
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