The impact of the microbiota on acute stress-induced monocyte trafficking

Authors: MOLONEY, GERRY - University College Cork; VAN DE WOUW, MARCEL - University College Cork; Lyte, Joshua - Josh; BOEHME, MARCU - University College Cork; DINAN, TIMOTHY - University College Cork; CRYAN, JOHN - University College Cork; CLARK, GERARD - University College Cork

Submitted to: Society for Neuroscience Abstracts and Proceedings
Publication Type: Abstract Only
Publication Acceptance Date: 6/20/2019
Publication Date: N/A
Citation: N/A

Interpretive Summary: Stress can very quickly cause activation of the immune system. Some of the immune-changes following stress include movement of immune cells from one location in the body to other locations and affect inflammation. The microbiota, which is a collection of bacteria, viruses, fungi, and other organisms that populate external body surfaces such as the skin and gut, have been shown to affect several body processes. Little is known, however, how the movement of immune cells may be affected by the microbiota. Understanding how the microbiota affect immune cell movement may provide a novel aspect by which to further understand and, potentially target, stress-induced inflammation. To investigate whether stress-induced changes in immune cell movement depend on the microbiota, we used germ-free (i.e. mice that are raised in sterile conditions and completely lack a microbiota) and conventional (i.e. mice raised in a normal environment) mice. Following a single, mild stressor we found that the immune cell movement response in germ-free and conventional mice was different. When germ-free mice were exposed to a normal environment and then stressed, the movement of immune cells appeared more similar to that of conventional mice. Our results suggest that stress-induced immune cell movement may be partly dependent on the presence of the microbiota. Further study is ongoing to examine how the microbiota may affect immune cell movement to influence inflammation.

Technical Abstract: It is well-known that acute stress induces activation of the immune system, resulting in a mobilization of immune cells. These changes are largely due to stress-induced increases in glucocorticoids and catecholamines. In particular, monocytes are affected as their prevalence decreases in the peripheral circulation, indicating stress-induced trafficking into other tissues. This is important as repeated acute stressors result in an enhanced monocyte trafficking into the brain, which is often associated with neuroinflammation. As such, understanding how we can modulate stress-induced monocyte trafficking might provide novel insights into how we can attenuate chronic stress-associated neuroinflammation. The microbiota has been implicated as a promising therapeutic target for modulating immune responses, and even brain physiology and behavior. As such, we wondered whether the microbiota could play a role in modulating acute stress-induced monocyte trafficking. Here we investigated stress-responses of male mice devoid of any bacteria (i.e., germ-free, GF), as well as GF mice colonized with a conventional microbiota (i.e., germ-free colonized, GFC). Mice were either sacrificed at baseline or underwent 15 minutes of restraint stress, after which they were sacrificed after 0, 45 or 240 minutes. Plasma corticosterone, adrenaline and noradrenaline was quantified using ELISAs. Blood and splenic monocyte subpopulations were quantified using flow cytometry. At baseline, GF mice showed elevated adrenaline, noradrenaline, and corticosterone levels, as well as decreased LY6Chigh and LY6Cmid monocytes, but not LY6Clow monocytes. Interestingly, all these changes were attenuated in GFC mice. Acute stress induced an increase in conventional, GF, as well as GFC mice. In response to acute stress, conventional mice showed an increase in circulating noradrenaline levels, which were absent in GF mice. Furthermore, stress-induced a decrease in circulating LY6Chigh and LY6Cmid monocytes, but not LY6Clow monocytes, which returned to baseline after 240 minutes in normal mice, but not GF and GFR mice. The same was observed for splenic LY6Chigh monocytes, which are known to be continuously stored and subsequently utilized in response to an immune stimulation. These results reveal novel kinetics of monocyte subtype-specific trafficking induced by acute stress, which shows a decreased recovery when the microbiota is absent and even after subsequent recolonization. Overall, these data show a promising role for the microbiota in modulating acute stress-induced monocyte trafficking, which could have important implications in chronic stress-associated neuroinflammation.