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Obesity-induced lymph node dysregulation - a TEM analysis

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Obesity is widespread and implicated in the development of metabolic diseases such as type II diabetes, CVD, and cancer. Excess adiposity has been demonstrated to induce a chronic low grade inflammatory state, which is linked to disease susceptibility. Previous studies demonstrate adipose tissue in mice consuming a high fat diet (HFD) have higher rates of macrophage (MO) infiltration. Resulting pro-inflammation occurs not only locally but also in the lymph nodes (LN) embedded in these fat deposits[1]. These areas, central to immune cell priming and maintaining homeostasis, link the innate and adaptive immune responses[2]. In our earlier investigation we hypothesized MO infiltration resulted in increased fibrosis in LNs and was associated with increased release of inflammatory cytokines IL-1β, CXCL8, and TNF by activated MOs [1]. These molecules are associated with increased fibrosis driving microarchitectural changes and subsequent dysfunction in several tissue types[3].

Claudia M. Solt, Kim G. Vanderpool* and Michelle T. Foster

Department of Food Science and Human Nutrition, *Biomedical

Science, Colorado State University, Fort Collins, CO, USA

CONCLUSIONS

Subjects: Male C57 BL6 mice were fed standard rodent

chow control (18% fat 33% protein 49% carbohydrate) or high fat diet (HFD) (western) (21% milk fat 34%sucrose, 45% kcal from fat, Harlan Teklad, Madison, WI) .

Termination: Occurred at 8 and >13 weeks. Visceral and subcutaneous lymph nodes and fat were collected.

Outcome Measures: Changes in lymph node architecture were examine with H& E and transmission electron microscopy. Cell numbers were quantified by flow cytometry.

METHODS

EXPERIMENTAL RESULTS

ACKNOWLEDGMENTS

Based on our findings mechanisms by which fibrosis interferes with cellular communication in the LNs is elucidated. Further exploration into the implications of fibrosis on HEVs and cell trafficking may enable us to comprehend the roles obesity and inflammation play in compromising conduit system integrity. Taken together this data can help support the development of preventative measures to reduce susceptibility to immune dysregulation associated with obesity.

Supported by DK087816

HFD LN microarchitecture was distinctly different from CHOW. CHOW SQLNs exhibited a pattern of closely packed lymphocytes interacting with APCs, including activated dendritic cells (DC), and MOs engaging in pseudopodia as evidenced by irregular MO shape. Collagen deposition in CHOW SQLNs was minimal. HFD SQLNs displayed active fibroblast reticular cells (FRCs) leaving large amounts of collagen creating physical barriers, which we postulate prevent lymphocyte and APC interaction. In addition, mast cells containing histamine granules were apparent in HFD SQLNs only. CHOW VLNs showed active phagocytic DCs and MOs interacting with lymphocytes. Plasma B cells were present, implicating a functioning conduit system. FRCs were inactive and collagen deposition is minimal, including surrounding area of the high endothelial venule (HEV). The HFD VLNs contained immature DCs, immobile MOs and highly active FRCs.

RESULTS

Figure 5 - Visceral Lymph Node

CHOW HFD

Figure 4- Subcutaneous Lymph Node

CHOW HFD

Visceral Lymph Node Border Visceral Lymph Node Center

Figure 3: 13 weeks of HFD induced significant fibrosis in visceral

lymph node. Fibrosis first appear in subcapsular space subsequently spreading to the paracortical T cell zone and medulla. (*p≤ 0.05, compared with respective control).

*

*

0.00E+00 5.00E+05 1.00E+06 1.50E+06 2.00E+06 2.50E+06 3.00E+06 3.50E+06 4.00E+06 4.50E+06 VLN VAT SLN SAT 8 W K VI AB LE C EL L COU NT CHOW HFD

RESULTS

*

*

0.00E+00 5.00E+05 1.00E+06 1.50E+06 2.00E+06 2.50E+06 3.00E+06 3.50E+06 4.00E+06 4.50E+06 VLN VAT SLN SAT 13 W K VI AB LE CEL L C OU NT Chow HFD

RESULTS

Figure 2 – Immune cell number A.) 8 weeks –HFD increased viable cells in VLN, visceral adipose tissue and SLN. B.) 13 weeks – HFD significantly decreased viable cells in VLN, but increased cell number in subcutaneous adipose tissue. (*p≤ 0.05, compared with respective control).

Visceral Lymph Node Subcutaneous Lymph Node a a a b 0.00E+00 5.00E+06 1.00E+07 1.50E+07 2.00E+07 2.50E+07 3.00E+07 3.50E+07 SQ Vis Ly m ph No de A rea (u m ) CHOW HFD Figure 1: HFD

increased the size of both visceral and subcutaneous lymph nodes at 8 weeks .

We hypothesized that the disruption of the LN conduit

system by fibrosis would affect immune cell

populations, activity, and the vital cell to cell cross talk that drives the immune response.

Figures 4 & 5 Key:

REFERENCES

DC MO Plasma cell FRC Collagen Mast cell T cell HEV

1.Magnuson, A. M. et al. Diet-induced obesity causes visceral, but not subcutaneous, lymph node hyperplasia via increases in specific immune cell populations. Cell Prolif. e12365 (2017). doi:10.1111/cpr.12365

2.Kim, C. S. et al. Visceral Fat Accumulation Induced by a High-fat Diet Causes the Atrophy of Mesenteric Lymph Nodes in Obese Mice. Obesity 16, 1261–1269 (2008).

3.Hadamitzky, C. et al. Age-dependent histoarchitectural changes in human lymph nodes: an underestimated process with clinical relevance? J. Anat. 216, 556–562 (2010).

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References

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