Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation

Westhaver, Lauren P.; Nersesian, Sarah; Nelson, Adam; MacLean, Leah K.; Carter, Emily B.; Rowter, Derek; Wang, Jun; Gala-López, Boris; Stadnyk, Andrew W.; Johnston, Brent; Boudreau, Jeanette E.

doi:10.1016/j.celrep.2022.110847

Cited by 14 publications

(15 citation statements)

References 66 publications

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“…(2022) , mitoDAMP preparations were characterized via liquid chromatography-mass spectrometry; a comprehensive list of the >550 unique proteins identified within mouse mitoDAMPs is available here . As expected, most proteins identified exist exclusively within mitochondria and are associated with mitochondrial processes ( Westhaver et al., 2022 ). This LCMS data were included as supplementary data in our manuscript and can be used to compare your results for quality assurance.…”

Section: Before You Beginsupporting

confidence: 64%

“…As described in Westhaver et al. (2022) , mitoDAMP preparations were characterized via liquid chromatography-mass spectrometry; a comprehensive list of the >550 unique proteins identified within mouse mitoDAMPs is available here .…”

Section: Before You Beginmentioning

confidence: 99%

“…This procedure produces μg quantities of mitoDAMPs and facilitates research to understand their impacts in health and disease. For complete details on the use and execution of this protocol, please refer to Westhaver et al. (2022) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Westhaver et al. (2022) .…”

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confidence: 99%

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Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue

Westhaver¹,

Nersesian²,

Nelson³

et al. 2022

STAR Protocols

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Section: Before You Beginsupporting

confidence: 64%

Section: Before You Beginmentioning

confidence: 99%

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Westhaver et al. (2022) .…”

mentioning

confidence: 99%

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Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue

Westhaver¹,

Nersesian²,

Nelson³

et al. 2022

STAR Protocols

Self Cite

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“…The clear signal in immune signaling pathways in our data, coupled with the lack of association between mitochondrial biomarkers and MeHg, indicates that the biological role of mitochondria in the response to MeHg is more complex than previously thought. For example, mitochondrial DAMPs may serve as a signal of self-damage that triggers endogenous suppression of inflammation to promote healing 142 . The high variance in both mitochondrial markers in both high and low exposure groups ( Fig.…”

Section: Discussionmentioning

confidence: 99%

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

Weinhouse

Perez

Ryde

et al. 2022

Preprint

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Background: Methylmercury (MeHg) is an environmental pollutant of global public health concern. MeHg is associated with immune dysfunction but the underlying mechanisms are unclear. The most common route of MeHg exposure is through consumption of fatty fish that contain beneficial n-3 polyunsaturated fatty acids (PUFA) that may protect against MeHg toxicity. Objectives: To better inform individual costs and benefits of fish consumption, we aimed to identify candidate epigenetic biomarkers of biological responses that reflect MeHg toxicity and PUFA protection. Methods: We profiled genome-wide DNA methylation using Illumina Infinium MethylationEPIC BeadChip in whole blood from N=32 individuals from Madre de Dios, Peru. Madre de Dios has high artisanal and small-scale gold mining activity, which results in high MeHg exposure to nearby residents. We compared DNA methylation in N=16 individuals with high (>10 μg/g) vs. N=16 individuals with low (<1 μg/g) total hair mercury (a proxy for methylmercury exposure), matched on age and sex. Results: We identified hypomethylated (i.e., likely activated) genes and promoters in high vs. low MeHg-exposed participants linked to Th1/Th2 immune imbalance, decreased IL-7 signaling, and increased marginal zone B cells. These three pathways are feasible mechanisms for MeHg-induced autoimmunity. In addition, we identified candidate epigenetic biomarkers of PUFA-mediated protection: hypomethylated enhancer binding sites for retinoid X receptor (RXR) and retinoic acid receptor α (RARα). Last, we observed hypomethylated enhancer and promoter binding sites for glucocorticoid receptor (GR), which is associated with developmental neurotoxicity, and transcription factor 7-like 2 (TCF7L2), which is associated with type 2 diabetes (T2D) risk. Discussion: Here, we identify a set of candidate epigenetic biomarkers for assessing individualized risk of autoimmune response and protection against neurotoxicity due to MeHg exposure and fish consumption. In addition, our results may inform surrogate tissue biomarkers of early MeHg exposure-related neurotoxicity and T2D risk.

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Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

et al. 2023

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The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39hi plasmablast metabolic reprogramming associated with adenosine‐mediated suppressive activity. Arginine deficiency has been linked to an increased risk of secondary infections in sepsis. Overcoming arginine shortage by citrulline administration efficiently improves sepsis‐induced immunosuppression and secondary infections in the cecal ligation and puncture murine model. Here, we aimed to determine the impact of citrulline administration on B cell suppressive responses in sepsis. We demonstrate that restoring arginine bioavailability through citrulline administration markedly reduces the dominant extrafollicular B cell response, decreasing the immunosuppressive LAG3+ and CD39+ plasma cell populations, and restoring splenic follicles. At the molecular level, the IRF4/MYC‐mediated B cell reprogramming required for extrafollicular plasma cell differentiation is shunted in the splenic B cells of mice fed with citrulline. Our study reveals a prominent impact of nutrition on B cell responses and plasma cell differentiation and further supports the development of citrulline‐based clinical studies to prevent sepsis‐associated immune dysfunction.

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Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation

Cited by 14 publications

References 66 publications

Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue

Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

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