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One corner stone of immunology is the principle by which the first immune cells at a side of infection produce messenger molecules that attract more immune cells. They signal for help. And not just that, the cells also “tell” the new arrivals what is going on and which action is needed – this includes pro-inflammatory responses to kill and contain the spread of the pathogen in the early stages of an infection, but also in later stages tissue-repair responses.
Askenase et al. now show that messenger molecules produced during acute gastro-intestinal infections can alter monocyte development in the bone marrow – that means molecules produced during inflammation cannot only influence cells close by but also cells far away in the bone marrow, which are still developing.
It’s been known for a while, that a higher number of immune cells egress from the bone marrow in response to systemic factors produced during infections. This mechanism, called emergency myelopoiesis, allows coping with the infection by providing more cells in circulation. What’s new in this study is the finding that factors produced in the gut during an acute Toxoplasma gondii infection can change the function of monocytes and not just their number.
Askenase et al. identified markers on the surface of specifically primed, regulatory Ly6Chigh monocytes known to produce IL-10 and PGE2 and thereby play a role in the clearance of T. gondii infection. These MHCII+/Sca-1+/CX3CR1– monocytes can be found in the gut six days post oral infection with the pathogen. Strikingly, primed monocytes can already be detected in the blood and bone marrow of infected mice four days post infection – long before the cells are recruited to the gut and any pathology can be found. Looking at monocyte precursors in the bone marrow, called cMoP, were shown to also be primed towards a regulatory phenotype – clearly indicating an effect of the infection on monocyte development in the bone marrow.
Investigating which messenger molecule can induce the priming of monocytes the authors found that injecting IFNγ into a normal mouse can switch blood monocytes to the same regulatory monocytes found in T. gondii infected mice. Concurringly, a block of IFNγ in T. gondii infected mice stops the switch of monocytes. This data indicate a major role for IFNγ in priming of bone marrow monocytes during infections. The problem is that the infection-induced increase of IFNγ levels in the blood does not start till five days post infection, which is after the switch of the monocyte phenotype in the blood and bone marrow is seen. To address this, the researcher hypothesised a local increase of IFNγ levels in the bone marrow. Indeed, co-staining for cell type-specific markers and IFNγ using microscopy demonstrated local production of IFNγ by NK cells in the bone marrow.
But how can NK cells sense that there is an infection ongoing in the intestine? One early systemic messenger molecule produced by dendritic cells in the intestine during T. gondii infection is IL-12, which is known to activate NK cells to produce IFNγ. By depleting NK cells and IL-12 during the infection, the author could show the importance of these cells and molecules, as the loss of both lead to decreased switching monocytes.
Overall this study nicely showed that infections have a wider effect on immune cells and aren’t limited to the side of infection. It also underlines the intricate and sometimes long signalling cascades used to send messages from one cell in one organ to a different cell in another organ and how signals a cell encounters early in development can have consequences on the subsequent function of cells.