Mincle Provokes Inflammation in Response to Microbes Leaking from the Aged Intestine
The aged intestinal wall exhibits an impaired mucosal barrier, leading to leakage of microbes from the intestines into tissues and circulatory system. This is known to provoke chronic inflammation, which in turn is disruptive to tissue function and contributes to the onset and progression of age-related conditions. Here, researchers identify one specific mechanism by which intestinal microbes can provoke the immune system into a maladaptive inflammatory response. Suppressing that response sounds like a worse option than preventing intestinal barrier dysfunction, as it would likely have negative consequences for immune function considered more broadly. Nonetheless, suppression of specific signaling remains the dominant approach to inflammatory conditions, even given side effects of this nature.
A new study shows how an increase in intestinal permeability allows the natural gut bacteria to cross the intestinal barrier and reach the bone marrow, where they induce epigenetic changes in the stem cells that give rise to immune cells. The epigenetic changes induced by the translocated gut bacteria generate "trained" immune cells primed to respond more efficiently to future infections. However, this same ability to amplify the immune response can also aggravate the inflammatory conditions such as cardiovascular and neurodegenerative diseases.
Until very recently, scientists believed that adaptive immunity was the only type with memory, able to generate cells that 'remember' previous encounters with pathogens and unleash a specific immune response. In contrast, the innate immune response, which is not specific to a particular pathogen, was believed to lack memory. "We now know that innate immunity can be 'trained' to produce a stronger response to later, unrelated infections. What is more, the effects of this training are long-lasting. The main intestinal bacteria we find in the bone marrow is Enterococcus faecalis. These bacteria interact with and activate the pattern recognition receptor Mincle in hematopoietic precursors, inducing epigenetic changes that generate immune cells with an augmented inflammatory capacity."
In animal models, increased intestinal permeability causes colonic inflammation (colitis). This inflammatory reaction does not occur in mice engineered to lack Mincle, suggesting that the detection of translocated bacteria by Mincle plays an important role in the inflammation associated with trained immunity. Strategies aimed at blocking Mincle could thus be protective in the context of these systemic inflammatory diseases.