Perforin deficiency in dendritic cells leads to overweight and metabolic syndrome

Dendritic cells (DCs) are both necessary for immunity and tolerance. While immunity part is more or less clear, DC's role in tolerance is not clear at all.

Here is another weird tolerogenic DC paper from Immunity. Here, the authors found that in BM chimera mice that lack perforin specifically in CD11^hi DCs develop a metabolic syndrome (obesity, insulin resistance and low glucose tolerance).

To tell you truth, this study should not be in Immunity. Journal of Immunology would have been better place. The problem is that the authors did not even bother to check any role of gut micirobiota in all these. But if you mention metabolic syndrome and did not check for gut microbiota, this is a cardinal sin for today's immunology.

In brief, the authors have generated mixed BM chimera mice wherein only DCs in mouse would be derived from BM cells lacking perforin (though having CD11c-driven Cre model would have been better alternative). Unexpectedly, the authors found that starting at 3 month these BM chimera mice become overweight.

The authors found that these mice with CD11c-specific perforin deficiency developed large adipose cells.

Finally, they showed that metabolic syndrome in these mice could be reversed by T cell depletion (but the authors have no data to explain why or how presence of T cells induces metabolic syndrome).

In summary, according to authors, this study suggests that when DCs lack perforin and are not able to eliminate T cells, this leads to accumulation of T cells that promote metabolic syndrome. What or how is not known. No words about gut microbiome.

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