"Nature": The mechanism that obesity "destroys" immunity has been found!

Obesity has a lot of disadvantages, and the cardiovascular and cerebrovascular diseases are exhausted
.

The red light for cancer risk is on, and the immune metabolism suffers the most
.

What is even more irritating is that sometimes the same drug, which is effective for normal weight people, is ineffective or even counterproductive for obese patients (emo)
.

But please don't give up treatment.
The magic height is one foot, and the road is one foot high.
Scientists have found that "immune fat reduction" can reverse this adverse effect
.

Today, a research team led by Sagar P.
Bapat, Ye Zheng and Ronald M.
Evans of the Salk Institute, and Alexander Marson of the University of California, San Francisco, published an important study in the prestigious journal Nature [1]
.

They found that obesity reshapes the body's immune status and alters the body's response to immunotherapy drugs.
In obese mice with atopic dermatitis, the immune inflammatory response that should have been mediated by Th2 cells turned into a Th17-mediated immune response.
Cell dominates
.

This shift not only caused the obese mice to exhibit a more severe inflammatory response, but also caused an otherwise effective treatment to become a "poison" that aggravated the condition
.

The good news is that they also found that PPARγ is the key to the above-mentioned shift in the immune response, and the PPARγ agonist (rosiglitazone) can "immune fat loss" in obese mice without changing their body weight, reversing this.
An adverse immune status
.

The findings not only shed light on how obesity alters the immune system, but also provide insights for clinicians to better manage allergies and asthma in obese people
.

There are many clinical studies showing that for a variety of immune inflammatory diseases, including atopic dermatitis and asthma, obese patients have relatively more severe symptoms and show resistance to treatments that are effective in normal-weight patients, but the potential The mechanism is not clear [2]
.

To gain a deeper understanding of the immunopathological effects of obesity, Bapat's team first constructed normal and obese (high-fat diet) mouse models of atopic dermatitis (vitamin D3 analog MC903 induced atopic dermatitis in mouse ears)
.

They found that the obese mice showed a more pronounced inflammatory response, with a 2-4 times increase in ear thickness and more severe dermatitis symptoms (erythema and scales) compared to the control mice.
The epidermal and dermal layers of the mice were more significantly expanded, and the number of leukocytes infiltrated was significantly increased
.

a.
The normal and obese (high-fat diet) mouse models of atopic dermatitis were constructed.
bd The obese mice showed a more pronounced inflammatory response.
Next, the Bapat team analyzed the T cells in the skin lesions by flow cytometry , found that compared with normal mice, the number of CD4+ T cells in the obese mice was significantly increased, and the numbers of regulatory T cells and CD8+ T cells also increased to a certain extent, suggesting an increase in the overall inflammatory response
.

Furthermore, in the CD4+ T cell subset, T cells positive for Th2 effector cytokines IL-4 and IL-13 did not significantly increase, while T cells positive for Th17 effector cytokines IL-17A and IL-17F increased, respectively 6.
5-fold and 11.
5-fold (P<0.
01)
.

This suggests that obesity may shift the inflammation that should be mediated by Th2 to an inflammatory response dominated by Th17
.

To further validate and analyze this shift, Bapat's team used single-cell RNA sequencing (scRNA-seq) to systematically study two groups of mice.
T cell sorting in murine dermatitis tissue
.

The analysis results showed that CD4+ T cells mainly included 4 T cell subsets (annotated as naïve, Th1, Th2 and Th17) and a group of circulating cells.
There were significant differences in the degree of differentiation of Th17 cells, and Th17 cells in normal mice were more in the "early" state (expressing the Th17 lineage transcription factor RORC, but not the effector cytokines IL17A, IL17f or IL22, and the cytokine receptor IL23r).
, while the majority of Th17 cells in the obese mice belonged to the "mature" state (expressing both RORC, effector cytokines and cytokine receptors)
.

There were significant differences in the distribution of cell subsets and the degree of Th17 cell differentiation between normal and obese mice.
Bapat's team also analyzed data from human allergic disease patients, including 59 patients with atopic dermatitis and hundreds of others.
Asthma patients
.

They also found that Th17 cells were more likely to dominate inflammation in obese patients than in normal people
.

These data suggest that, in both humans and mice, obesity leads to a shift in immune status that leads to altered pathology of inflammatory diseases
.

Because of the abnormal Th17-mediated inflammatory response in the obese mice, Bapat and colleagues strongly suspect that a therapeutic approach by blocking the Th2 cell effectors IL-4 and IL-13 (which has been shown to be effective in the treatment of Th2-driven It is very effective for severe allergic diseases, such as asthma, sinusitis, atopic dermatitis, etc.
[3-5]), whether it can have a therapeutic effect on the obese mice
.

After treating both groups of mice with neutralizing antibodies against IL-4 and anti-IL-13, Bapat's team found that, as expected, anti-IL-4/IL-13 treatment had a significant effect on the normal group of mice and Mice in the obese group were ineffective and even aggravated symptoms (symptoms of severe atopic dermatitis such as small pustules)
.

Surprisingly, the number of IL-17F-positive cells in the obese mice increased after anti-IL-4/IL-13 treatment, suggesting that anti-IL-4/IL-13 blocking Th2 cell therapy aggravated the obese mice.
Inflammatory responses mediated by non-Th2 cells
.

Anti-IL-4/IL-13 treatment has a significant effect on the normal group of mice, but it is ineffective for the obese group of mice, and even aggravates the symptoms.
What is the reason for the abnormal immune state of the obese group of mice? Bapat and his colleagues analyzed the scRNA-seq data and found that in normal mice, genes related to PPARγ (belonging to the nuclear hormone receptor superfamily and important for regulating Th2 cell function) were highly expressed in Th2 cells, However, expression of these genes was reduced in obese mice
.

This indicated that PPARγ activity was decreased in Th2 cells of obese mice
.

In contrast, there was no significant difference in PPARγ-related gene expression in Th17 cells of the two groups of mice
.

These findings suggest that the normal expression of PPARγ may play an important role in maintaining the inflammatory response dominated by Th2 cells, and the impaired function of PPARγ in Th2 cells in obese mice favors other Th-type cells to mediate inflammatory responses
.

To test this idea, Bapat's team constructed T cell-specific PPARγ-deficient mice (PPARγ-TKO mice)
.

After induction of atopic dermatitis by MC903, PPARγ-TKO normal-weight mice developed dermatitis symptoms similar to wild-type obese mice
.

Both flow cytometry and scRNA-seq showed that PPARγ-TKO normal weight mice were mainly mediated by Th17 cells, and anti-IL-4/IL-13 treatment also aggravated the atopy of PPARγ-TKO mice.
Dermatitis symptoms
.

These results strongly support that PPARγ is a factor critical for maintaining Th2 cell-mediated inflammatory responses in vivo
.

That is to say, it is the "body control" of PPARγ (working hard in normal-weight mice and lying dead in obese mice) that drags down the T cells of the obese group
.

PPARγ-TKO normal body weight mice are dominated by Th17 cell-mediated inflammatory responses Finally, Bapat's team tried to use the PPARγ agonist rosiglitazone (which has been approved by the US FDA for the treatment of type 2 diabetes) to remodel the obesity group.
Murine immune cell-mediated inflammatory states
.

After experiments, it was found that PPARγ agonist treatment can significantly reduce the symptoms of dermatitis in obese mice, and restore the inflammatory response mainly mediated by Th2 cells in the skin lesions, making anti-IL-4/IL-13 treatment effective for obesity.
Group mice were effective
.

Rosiglitazone can reshape the inflammatory state mediated by immune cells in obese mice, allowing anti-IL-4/IL-13 treatment to regain efficacy in obese mice.
Overall, this study by Bapat's team shows that, Obesity can cause the inflammatory state in atopic dermatitis to change from Th2 cell-mediated to Th17 cell-dominated, resulting in changes in the clinical symptoms of the disease and abnormal response to originally effective treatments
.

More importantly, Bapat's team found that this immune cell state can be changed, and approved PPARγ agonists (such as rosiglitazone) can reshape the body's immune state and perform "immune fat reduction"
.

These results will help fast-track FDA-approved drugs into the clinic and provide better treatment options for obese patients with allergies and asthma
.

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.

In this column, we will show you the splendid beauty under the super microscope
.

The first issue, welcome to watch the snow together
.

Reference 1.
Bapat SP, Whitty C, Mowery CT, Liang Y, Yoo A, Jiang Z, Peters MC, Zhang Lj, Vogel I, Zhou C et al: Obesity alters pathology and treatment response in inflammatory disease.
Nature 2022.
2.
Silverberg JI, Gelfand JM, Margolis DJ, Boguniewicz M, Fonacier L, Grayson MH, Simpson EL, Ong PY, Chiesa Fuxench ZC: Patient burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study.
Ann Allergy Asthma Immunol 2018, 121(3):340-347.
3.
Hearn AP, Kent BD, Jackson DJ: Biologic treatment options for severe asthma.
Curr Opin Immunol 2020, 66:151-160.
4.
Laidlaw TM, Bachert C, Amin N, Desrosiers M, Hellings PW, Mullol J, Maspero JF, Gevaert P, Zhang M, Mao X et al: Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma.
Ann Allergy Asthma Immunol 2021, 126(5) :584-592 e581.
5.
Tubau C, Puig L: Therapeutic targeting of the IL-13 pathway in skin inflammation.
Expert Rev Clin Immunol 2021, 17(1):15-25.
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