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Science—Heavy! A history of obesity induces epigenetic changes in the innate immune system and exacerbates neuroinflammation

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Written by Jane Cheng – Wang Sizhen, Fang Yiyi edited – Wang Sizhen
age-related macular degeneration （age-related macular degeneration， AMD) is a neuroinflammatory disease that is influenced by genetic and environmental factors, such as obesity, and is also a leading cause
of blindness.
In the early days of AMD, insoluble deposits of drusen appeared in the subretinal pigmented epithelium (RPE) space, mainly composed of lipids, proteins, hydroxyapatite, and trace metals
。 Microglia, macrophages, and monocytes of the retina are recruited to clear drusen; If the hydological wart cannot be removed in time and completely, it will further trigger pathological inflammation and angiogenic reactions, resulting in tissue damage and the development of advanced AMD [1,2].

There are two forms of advanced AMD, neovascular AMD (nAMD, also called "exudative") and non-neovascular AMD ("atrophic AMD") ）
。 Among them, nAMD can cause vision loss in more than 80% of AMD patients, and its pathological feature is the growth of abnormal choroidal blood vessels under the macula, called choroidal neovascularization ( choroidal neovascularization，CNV）
。 In addition to the local immune response, the progression of AMD is affected
by increased inflammation throughout the body.
How systemic inflammation affects AMD remains to be elucidated
.
Studies have shown that the volume of visceral adipose tissue in nAMD patients is significantly increased; For every 0.
1 increase in waist-hip ratio, the chance of advanced AMD increases by 75%; Higher body mass index (BMI > 30) is associated with advanced AMD progression and years of illness [3-5], and these clinical findings suggest that obesity or overweight may accelerate the progression of advanced AMD, however The mechanism is unknown
.

On January 6, 2023, Przemyslaw Sapieha's team from the University of Montreal published a title in Science “Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation” Through techniques such as transposase-accessible chromatin (ATAC-seq), ChIP-qPCR, and flow cytometry sorting, it is revealed that early diet-induced obesity triggers innate immune system reprogramming, and this apparent alteration persists even after weight loss or normal metabolism
。 Stearic acid binds to Toll-like receptor 4 (TLR4), which reshapes the chromatin map and selectively enhances the accessibility of activating protein 1 (AP-1) binding sites.

Oxidative phosphorylation of bone marrow cells transitions to glycolysis, eventually leading to pro-inflammatory cytokine transcription, pathological retinal angiogenesis abnormalities, and optic nerve degeneration
.
The study demonstrated that a history of obesity reprograms mononuclear phagocytes, making individuals more susceptible to neuroinflammation
.

First, the researchers established the Weight Gain-Loss (WGWL) experiment, male C57BL/6J Mice are subjected to 11 weeks of high-fat diet (HFD: 60% lipid content) to induce obesity, after which they are switched to a regular diet (RD: 10% lipid content) for 9 weeks to lose body weight (HFD-RD mice), and weight is measured at two time points, Glucose tolerance (GTT) and insulin resistance (ITT) experiments found that weight gain, glucose tolerance, and insulin tolerance caused by HFD returned to normal after switching to a normal diet (Figure 1A-G).

。 CNV modeling is performed with laser irradiation of mouse eyes after 20 weeks of feeding, and detection is performed after two weeks
.
It was found that the CNV of HFD-RD mice increased by 40% (FITC signaling) (Figure 1 H-K), IB4 There was no difference in the average size of the labeled lesion area between groups, indicating that the observed effect acted directly on the neovasculature (Figure 1 J-K), with no difference in the number of mononuclear phagocytes (MNPs) and microglia (IBA1) in the two groups of mice (Figure 1 H&L).

The above results suggest that a history of obesity has a long-term effect on individuals, manifested by enhanced new vascularization in retinal tissue, without affecting the number of
MNPs associated with lesions.

Figure 1: </b2 caused by a high-fat diet1> Changes GTT and ITT and CNV

(Source: Hata M, et, al.
, Science, 2023).

Given that adipose tissue is one of the largest immunoactive organs and changes in form and function during obesity, the researchers tested adipose tissue from mice with a history of obesity for pathogenicity
.
The researchers performed adipose tissue transplantation (ATT), transplanting 500 mg of visceral white adipose tissue (eWAT) from RD-RD mice or HFD-RD mice into C57BL/6J recipient mice (Figure 2M).

Postoperative testing revealed that the graft was normal and there was no necrosis of vascularization (Figure 2N).

Three weeks after transplantation, recipient mice receive laser-induced CNV
.
Mice transplanted with HFD-RD ATT produced more CNV (Figure 2 O-R) than RD-RD ATT recipient mice or sham surgical mice, recruiting MNP to the site of injury There was no significant difference in quantity between groups (P = 0.
55) (Figure 2S).

In conclusion, the above results showed that despite the normal return of body weight and metabolism, the fatty tissue of mice with a history of obesity could still promote pathological neovascularization
.

Figure 2 Effect of ATT on CNV (Source: Hata M, et, al.
, Science, 2023).

Why does adipose tissue have the memory to promote pathological neovascularization? The researchers further analyzed and found that the size and distribution of adipose tissue in HD-RD mice changed, and adipose tissue macrophages (ATM) in adipose tissue macrophage (ATM, including F4/80+, EMR1+) in adiposetissue 、 CD11b+, CD38+) is 3 times higher than RD-RD mice (Figure 3F-I).

To further examine how ATM affects CNV, the researchers will come from LysM^cre⁺:Ai3^EYFP+ Mice (monocytes, mature macrophages, and granulocytes are labeled with fluorescence (Figure J) adipose tissue is transplanted into normal mice and CNV
is induced after 3 weeks.
It was found that the fluorescently labeled cells at the CNV site increased significantly, indicating that adipose tissue-derived myeloid cells directly infiltrated the CNV lesion site and promoted inflammation and disease progression
.

Figure 3: Adipople-derived myeloid cells directly infiltrate the site of CNV lesions and promote inflammation (Source: Hata M, et, al.
, Science, 2023)
The researchers then evaluated bone marrow from RD-RD mice and HFD-RD mice using real-time quantitative PCR (RT-qPCR).
， BM) isolated transcription levels of innate immune-related genes in monocytes and found interleukin1b (Il1b) and Il6 in HFD-RD mice compared to RD-RD controls Significantly elevated (Figure 2M).

To test whether BM in mice with a history of obesity could promote CNV progression, the researchers performed a bone marrow transplant (BMT) experiment to combine the BM of HFD-RD (CD45.
2) mice Transfer transfer to lethal irradiation to B6.
SJL (CD45.
1) Recipient mice (Figure 4N).

After eight weeks of BMT, the circulating monocytes population expresses the allele of the donor mouse's pan-hematopoietic cell marker CD45, demonstrating successful transfer (Figure 4O).

When chimeric mice receive laser-induced CNV 8 weeks after BMT, mice that receive BMT in HFD-RD mice than those that receive Mice with RD-RD BMT produce more CNV (Figure 4 P-Q).

Thus, transplantation of myeloid cells in mice with a history of obesity reshapes adipose tissue and drives CNV
.

Figure 4: Myeloid cells from mice with a history of obesity remodel adipose tissue in normal mice and induce CNV (Source: Hata M, et, al.
, Science, 2023)
Next, the researchers used ATAC-Seq sequencing to analyze ATM in obese mice caused by a high-fat diet epigenetic changes
.
The results showed that the gap between RD-RD mice and HFD-RD mice had the largest ATM, with 4989 differential accessibility regions (DARs).
(Figure 5D).

2022 DARs present in RD-R D V.
S HFD-RD mice instead of RD-RDV.
S HFD-RD mice, validated History of obesity affects the sustainability of ATM epigenetically
.

Figure 5 Epigenetic differences in AMT caused by fatty foods (Source: Hata M, et, al.
, Science, 2023).

Further functional GO analysis found "angiogenesis" and "inflammatory response" of gene concentration, HFD_RD A P-1 targeting gene of mouse ATM, such as Il1b, kappa in B cells Nuclear factor 1 (Nfkb1), Tnf α-inducible protein 3 (Tnfaip3), vascular endothelial growth factor A ( Vegfa), angiopoietin-1 (Angpt1), platelet-derived growth factor receptor (Pdgfr), and β peptide (Pdgfrb) have high accessibility, while Il10 accessibility is low (Figure 6G), the results of Bioinformation analysis were further validated in mouse experiments (Figure 6 I-P).

These results suggest that a history of obesity leads to persistent pro-inflammatory changes in visceral adipose tissue and an increase in systemic inflammation
after experimental injury.

Fig.
6 Differences in pro-inflammatory and proangiogenic factors between different groups of mice (Source: Hata M, et, al.
, Science, 2023).

Which lipids in HFD drive epigenetic changes? The researchers performed quantitative fatty acid (FA) analysis on RD-RD and HFD_RD mice using gas chromatography-mass spectrometry (GC-MS) and found that stearic acid (SA, C18:0) was found to be in the process of stearic acid HFD increases significantly during and returns to normal levels after returning to a normal diet (Figure 7 A-B).

Figure 7 High-fat foods cause changes in various fatty acids in serum (Source: Hata M, et, al.
, Science, 2023
Is SA involved in persistent changes in adipose tissue? The researchers isolated myeloid macrophages, added SA incubation for 24 h and then administered LPS for 5 consecutive days to find myeloid macrophages (BMDM) pretreated with SA of Increased expression of mRNA from Tnf, Tnfaip3, Il6 and Nfkb (Figure 8C-D).

This alteration was not present in TLR4-knocked mice (Figure 8 E-F), indicating that SA binding to TLR4 receptors mediates BMDM Changes
in response to LPS.

Fig.
8 Effect of SA pretreatment on BMDM cells responding to LPS stimulation (Source: Hata M, et, al.
, Science, 2023 ）
Since cellular energy metabolism affects cell phenotype and function [6], the researchers speculate whether SA induces innate immune memory mechanisms
by altering BMDM metabolism.
By comparing the oxygen consumption rate of BMDM in the control group (BSA) and the SA pretreatment groupmption rate, OCR), OCR discovery before and after LPS stimulation, BMDM pretreated in SA Decreased basal and maximal respiration volume (Figure 9 L-N); The BMDM glycolysis pathway was enhanced by comparing extracellular acidification rates (ECARs) (Figure 9 O-Q) The above results suggest that the history of obesity can form innate immune memory by altering the energy metabolism program of BMDM.

Fig.
9 SA increases BMDM glycolysis and decreases oxidative metabolism (Source: Hata M, et, al.
, Science, 2023).

Finally, based on the results of ATAC-Seq bioinformation analysis, the researchers found AP-1 in ATM of HD-RD mice Increased accessibility to transcription factor family binding sites, including c-JUN, c-FOS, and ATF
.
After hypergeometry optimization based on motif rich (HOMER) motifs, it is found that the top eight highest motifs correspond to the binding sites of AP-1 family members
.
It has been shown that AP-1's own binding can lead to chromatin remodeling
by recruiting histone modifying enzymes that trigger pro-inflammatory genes.
Therefore, the researchers next examined whether c-JUN (a major component of the AP-1 family) and histone acetyltransferase (HAT) were recruited onto the Tnf gene promoter after SA exposure (Figure 10D).

The results showed that stimulation of BMDMs with SA for 1 h increased phosphorylation of c-JUN (Figure 10 E-G).

Chromatin immunoprecipitation (ChIP)-qPCR analysis showed an increase in c-JUN and EP300, lysine 27 (H3K27ac) in cells treated with SA, recruited into the promoter region of the Tnf gene Significant increase in upper histone H3 acetylation (Figure 10 H-J).

These results suggest that the mechanism of macrophage reprogramming may be chromatin remodeling at the AP-1 site bound to SA.

Figure 10 Chromatin remodeling of BMDM AP-1 binding site by SA pretreatment (Source: Hata M, et, al.
, Science, 2023)
Article conclusion and discussion, inspiration and prospects

In conclusion, this study found that a history of obesity has the potential to induce long-term chromatin remodeling in tissue-resident myeloid cells such as ATM, resulting in different myeloid cells (such as ATM and retinal microglia) being more likely to trigger proangiogenic and pro-inflammatory responses, and these cells may exacerbate inflammation even if weight and metabolic status have returned to normal.
Eventually exacerbates neuroinflammation
following experimental injury to distant tissues such as the retina.
Persistent changes in the chromatin profile of innate immune cells exacerbate pathological angiogenesis and neuronal degeneration in experimental models, suggesting a link
between systemic innate immunity and retinal disease.
Thus, treatments that target epigenetic reprogramming of the innate immune system or eliminate reprogramming subsets of innate immune cells may delay or prevent the progression of neovascular age-related macular degeneration (AMD) and non-neovascular AMD.

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