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New study! Learning about inflammation by studying the differences between mammals – a toot-orial.
https://doi.org/10.1186/s10020-024-01052-x
When the body meets an infectious microbe or similar challenge it activates an inflammatory cascade. Inflammation helps eliminate the microbe, but, if it gets of control, it can be dangerous or even fatal.
We like to assume that inflammation is basically the same for all animals. And this is usually true in cell culture, but in vivo …
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“Mice lie and monkeys don’t always tell the truth.”
Mice can survive injection with hundreds- or thousands-fold more bacterial product than would kill a human. Some monkeys are also very resilient but rabbits and sheep are sensitive, like humans.
This is a problem. Are all the studies where people have injected LPS into mice and monkeys to study inflammation irrelevant?
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But, wait – mice have healthy and robust immune systems. They can resist bacterial and viral infections at least as well as humans, and aren’t especially prone to cancer. So how do they do that without risking the runaway, systemic inflammation that can kill a human?
Might it possible to treat patients so that they don’t suffer excessive inflammation while still fighting off infections?
We set out to find out what causes the difference.
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We took blood from 10 different species of mammal with very different susceptibility to lethal inflammation, and measured the gene expression in the white blood cells as well as lipids and proteins in the plasma. We measured both naïve blood and blood after ex vivo stimulation with LPS.
We used the same reagents and protocol for all our species to control against batch effects and experimental factors that plague attempts to compare comparison of omic datasets.
4/
We didn’t find many differences in the lipidome or proteomes that correlated with sensitivity to inflammation. But in the transcriptomes ….
Leukocytes from resilient and sensitive species respond differently to LPS, including by genes involved in LPS detoxification and metabolism.
Most surprisingly, even without stimulation, we could distinguish sensitive species from resilient ones.
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Compared to resilient cells, the transcriptomes of sensitive cells showed a more inflammatory phenotype, as though they had already been stimulated with LPS. The biggest differences tended to be in genes that aren’t themselves LPS responsive but encode proteins that mediate inflammatory signalling, such as Myd88 and other members of the #TLR cascade.
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It will be important to understand how these differences in gene expression contribute to regulation of inflammation and susceptibility to systemic inflammation. Interventions that modulate inflammation to produce a “mouse-like” phenotype could be a powerful new therapeutic strategy for acute inflammatory diseases like #sepsis, #SIRS, or #shock.
https://doi.org/10.1186/s10020-024-01052-x
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