Pregnancy-associated microbiota modules newborn's group 3 innate lymphoid cells (ILC3)

It is common believe that newborns are born sterile and their immune system undergoes changes at post-natal period in response to their own microbial exposure.

However, new study in Science challenges this concept by showing that mother's microbiota during pregnancy has permanent impact on offspring's postnatal innate immune system. 

To distinguish effects of maternal vs. neonatal microbiota on neonate's immune system, the authors used a "system in which pregnant dams are transiently colonized with genetically engineered Escherichia coli HA107", a E. coli strain that does not persist in the host and "pregnant dams become germ-free again before term and naturally deliver germ-free pups". Compared to control, microbiota-nil pregnant females, offsprings derived from temporally colonized pregnant females contained more IL-22 producing intestinal ILC3 (there was no effect on T or B cell numbers).

Maternal microbiota effect on newborn's ILC3 numbers could be reproduced by injecting germ-free pregnant females with serum (IgG) derived from HA107 colonized females (though it is not clear whether microbiota-specific IgG or any random IgG could produce the same effect).

Similarly, maternal microbiota effect on newborn's ILC3 numbers was lost in pregnant females lacking B cells (Ig_H^-/-).

In summary, this study suggests that pregnancy-associated microbiota does have an independent effect on maturation of newborn's innate immune system, at least via maternally-derived antibodies.

David Usharauli

PGE2-IL-22 axis prevents gut microbiota leakage during systemic inflammation

This week Science published interesting study showing cooperation between prostaglandin E2 (PGE2), one of the most abundantly produced prostaglandin, and innate lymphoid cell (ILC3)-produced IL-22 in keeping gut barrier tight during systemic inflammation (e.g. bacteremia, sepsis, and septic shock).

This is very neatly done study. In the initial experiments, the authors showed that pre-treatment of mice with indomethacin (which suppresses PGE2 production) increased their susceptibility to systemic inflammation following endotoxin (LPS) injection.

Interestingly, when mice were also pre-treated with EP4 agonist (PGE2 receptor), it reduced systemic inflammation following LPS injection. 

Moreover, beneficial effect of EP4 agonist on systemic inflammation following LPS injection was mimicked by antibiotic pre-treatment, suggesting the role of gut barrier in protection mediated by PGE2.

Indeed, EP4 agonist pre-treatment prevented bacterial translocation from gut into sterile internal tissues such as liver.

Finally, the authors showed that PGE2-EP4 signaling in group 3 innate lymphoid cells was necessary for IL-22 production that contributed to maintaining gut barrier function during systemic inflammation (of note, EP4 agonist had (a) no effect in IL-22KO mice and it was still active in (b) RAG KO mice that lack adaptive immune system).

In summary, this study provided additional support for innate cell-derived IL-22 as a cytokine necessary for keeping gut tissue in healthy condition.   

David Usharauli

IL-22 promotes intestinal integrity via direct effect on stem cells

In this new paper published in journal Nature the authors showed that cytokine IL-22 promotes intestinal integrity and regeneration potential in GvHD via its effect on Lrg5+ intestinal stem cells (ISC).   

Initially, the authors showed that IL-22 produced by group 3 innate lymphoid cells (ILC3) promoted in vitro growth of intestinal organoids (small intestine crypt cells cultured with EGF, Noggin and R-spondin-1, ENR).

Growth augmentation by IL-22 was mediated via STAT3 signaling, as shown by growth defect of STAT3 KO crypt cells cultured with IL-22.

Unlike Paneth cell depletion, experiments with  Lrg5⁺ stem cell depletion confirmed that IL-22 promoted intestinal regeneration via its effect on stem cells (though I don't know whether organoids growth could happen without  Lrg5⁺ cells, in the first place).

Finally, the authors conducted in vivo experiments with rh IL-22 to validate hypothesis that IL-22 or its analog could improve survival in GvHD (condition that leads to intestinal damage). Indeed, treatment of mice with stabilized rhIL-22 analog, F-652, following bone marrow transplantation (BMT), reduced intestinal damage and improved host survival (though mrIL-22 effect was less dramatic in Fig 3).

In summary, this study suggests that IL-22 could provide therapeutic benefits in medical conditions where gut integrity is compromised.

Note: the authors claim that they filed a provisional patent application "on the use of IL-22....as ISC growth factor". I don't believe one could get any patent on naturally occurring products, such as IL-22. In addition, idea that IL-22 affects gut epithelia is well established concept. While the authors refined this concept and showed that IL-22 may work directly on stem cells, this by itself is not a patent-eligible innovation, in my view.

David Usharauli

Stress-release with IL-22

Type II Diabetes (T2D) is part of a complex metabolic syndrome. Typically, conditional insulin deficiency as observed during T2D is a result of an imbalance between production and demand for insulin. I always wondered why would nature develop such a system where packaging of excess glucose would be controlled by a single molecule (insulin), while glucose unpacking, it's release into bloodstream are controlled by so many molecules, including corticosteroids.

Prevalence of T2D is increasing in modern population. Speculation varies as to the cause of such increase in T2D (availability of excess food, poor physical activity, widespread use of broad-spectrum antibiotics causing changes in gut microflora, etc).

Frequently the metabolic syndrome is associated with the changes in immune cytokines. Occasionally, immune cytokines are directly implicated in disease, for example IL-17 and TNF-alpha in psoriasis or rheumatoid arthritis.

On other hand, the list of immune cytokines are constantly expanding and maybe some of them would show a beneficial effect.

This new paper in Nature Medicine is one such research. This study, led by Michael McGuckin from the University of Queensland (Australia), has uncovered the protective role for cytokine IL-22 in T2D. 

IL-22 is a member of IL-10 cytokine super-family that includes IL-10, IL-22, IL-24, IL-26, so far.

Using in vitro assay to measure beta cell ER stress, the authors showed that IL-23, IL-24, IL-33 were the potent inducers of ER stress.

Parallel experiments with beta cell exposure to the pairwise combination of cytokines revealed that IL-22 (and IL-10) could reverse ER stress caused by any other cytokines examined, including IL-23, IL-24, IL-33. Two exceptions were IL-17A for IL-22 and IL-17F for IL-10 for which the effectiveness of such inhibition were less prominent.

As a consequence of reduced ER stress, IL-22 was able to improve secretion of insulin from primary mouse beta islets.

Importantly, using high-fat diet induced obesity mouse model (HF-DIO mouse), the authors showed that in vivo treatment with IL-22 could reduce beta cell ER stress and reverse decline in insulin secretion in response to HF diet.

In addition, IL-22 treatment could reverse high-fat diet effect on body weight and glucose tolerance.  

Mechanistically, this beneficial effect of IL-22 was associated with decrease in ER-stressor inflammatory cytokines and in increase for enzymes responsible for neutralization of free radicals.

Finally, the authors showed that this beneficial effect of IL-22 could be reproduced in an in vitro experiments with human beta islets as well.

In summary, this figure-packed research showed that IL-22 can have a protective characteristics beneficial for management of beta cell functions.

It is not immediately clear why immune cytokines play such important roles in non-immune functions. For example, why would IL-23 induce beta cell stress and reduce insulin secretion? Similarly, it is not clear why IL-22 would develop protective function for beta cells. Previous studies showed that IL-22 has a protective role in gut epithelial cell function (probably through it's effects on cell surface fucosylation). On the other hand, IL-22 has been implicated in promoting skin epithelial hyper-proliferation characteristic to psoriasis. So, the field is quite confusing, to say the least.

David Usharauli