Gut-specific eosinophils suppress IL-17 production by antagonizing IL-1 signaling

Prior to discovery of Toll-like receptors (TLR) in late 90s, immunology was dominated by concepts involving adaptive immune cells. However, for past 15 years it has become evident that innate immune cells of "all shapes and forms that exist out there" are equal partners with T and B cells and frequently provide instructions and actually control the magnitude and directions of adaptive immune response. For example, development of successful, next generation vaccines would require incorporation of these new concepts. 

It seems innate immune system is even more complex and unpredictable than T or B cells are. For instance, this week Journal of Experimental Medicine published new study wherein the authors reported that eosinophils, a cell population usually implicated in allergy and anti-helminth response, suppressed Th17 cells by antagonizing IL-1 signaling.

First, the authors observed that Th17 cells in ΔdblGATA-1 mice [which lack eosinophil-lineage cells] were significantly increased in the small intestine, but not in the spleen or mesenteric LNs (MLNs).

In vitro generation of Th17 cells were inhibited by presence of small intestinal eosinophils. 

Functional profiling revealed that small intestinal eosinophils secreted high amount of IL-1 receptor antagonist (IL-1Ra), which competes with IL-1β for receptor binding (IL-1 signaling is involved in Th17 development).

Interestingly, eosinophils were the major producers of IL-1Ra in small intestine, since no IL-1Ra was detected in small intestinal tissue from ΔdblGATA-1 mice. Of note, eosinophils from blood or bone marrow produced little or no IL-1Ra. 

In addition, the authors showed that small intestinal eosinophils derived from MyD88-KO or Germ Free (GF) mice produced WT-level IL-1Ra, suggesting its independence from gut flora or major TLR signaling.

Role of IL-1Ra in eosinophil mediated Th17 suppression in small intestine was confirmed in experiments with eosinophils derived from IL-1Ra-KO mice.   

In summary, this study showed that small intestine harbors specialized eosinophils secreting high amount of IL-1Ra and suppressing steady-state development of Th17. 

David Usharauli

Commensal virus to the rescue

We all heard about gut microbiome and how an important job they do to keep us healthy. Still, there is the situations when the antibiotic therapy is necessary. 

Since many beneficial microbes in our gut are sensitive to broad spectrum antibiotics used in today's medicine, such treatment could lead to dysbacteriosis and gut inflammation. Now, beneficial microbiome therapy (fecal transplantation) is an obvious option, but such therapy could be inefficient due to the fact that such flora itself is sensitive to antibiotics. So what is the solution?

It appears that some friendly viruses in the gut could provide such beneficial, cover effect. Such study, led by Ken Cadwell from New York University School of Medicine, was recently published in journal Nature.

The authors studied the murine norovirus (MNV). This virus is endemic in laboratory mice colonies but does not produce an overt gut inflammation in a immune-competent host. 

Reconstitution of germ-free mice with MNV produced changes in the gut morphology and immune cells resembling conventional mice gut. 

More relevant, MNV could reverse antibiotic-induced negative effects on gut immune system.

Mechanistically, such beneficial effect of MNV on gut immune system was type I IFN dependent.

Finally, MNV could prevent antibiotic-induced gut sensitivity to chemical damage (DSS).

In summary, the authors showed that viral therapy could be an viable alternative (since virus would not be sensitive to antibiotic itself) to treat or prevent antibiotic-induced gut immune malfunctions.

Of course, application of this study to human population would require additional research. 

First, human Norovirus is clearly not a benign virus (cruise ship virus). So we need to find the virus that does not induce an overt gut inflammation in healthy humans. 

Second, this study examined immune-competent mice. However, analyses of immune-deficient mice responses to NMV would be more informative since in humans, antibiotic therapies are frequently used to compensate for immune deficiencies.

Third, if gut commensal, beneficial viruses exist, they should naturally (automatically) take over the beneficial microbes functions during antibiotic treatment. Do they do it?

Fourth, recent studies indicated that viruses, including MNV, require the presence of bacteria for their infectivity. How this knowledge affects the results of this study is to be determined.

David Usharauli