Arginine-Glycine-Aspartic Acid-anchored Curcumin-based Nanotherapeutics Inhibit Pyroptosis-induced Cytokine Release Syndrome for <i>In Vivo</i> and <i>In Vitro</i> Sepsis Applications

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Abstract

Aim

We aimed to design RGD-anchored liposomes encapsulating an antipyroptosis drug that could efficiently target macrophages and relieve the rate of cytokine release syndrome, providing a new strategy for sepsis treatment, especially sepsis-induced acute renal injury.

Background

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by host response disorders due to infection. Sepsis has a high incidence and remains one of the leading causes of death worldwide.

Objective

Macrophage-mediated pyroptosis plays an important role in the occurrence and development of cytokine release syndrome and organ injury caused by sepsis. Curcumin can inhibit inflammasome assembly and slow the progression of pyroptosis by scavenging intracellular reactive oxygen species, but it has poor water solubility and low bioavailability. The emergence of drug-delivery nanosystems has overcome this problem, but there is still a lack of research on how to accurately deliver antipyroptotic drugs to innate immune cells and subsequently hinder pyroptosis.

Methods

We constructed a curcumin-loaded RGD-modified liposome (RGD-lipo/Cur) and demonstrated that RGD-lipo/Cur could effectively target macrophages.

Results

In vitro, RGD-lipo/Cur reduced the upregulation of caspase-1, caspase-3, NLRP3, IL-1β and GSDMD, inhibiting pyroptosis, reducing oxidative stress, and attenuating the proinflammatory cytokine cascade.

Conclusion

RGD-lipo/Cur was considered to have great potential for sepsis treatment.

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Most cited references 32

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The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

Mervyn Singer, Clifford S Deutschman, Christopher Warren Seymour … (2016)

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

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Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

Kristina Rudd, Sarah Charlotte Johnson, Kareha M Agesa … (2020)

Summary Background Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. Methods We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. Findings In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. Interpretation Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. Funding The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

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Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

Wan-ting He, Haoqiang Wan, Lichen Hu … (2015)

Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd −/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd −/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.

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Author and article information

Journal

Journal ID (publisher-id): CPD

Journal ID (nlm-ta): Curr Pharm Des

Title: Current Pharmaceutical Design

Abbreviated Title: Curr. Pharm. Des.

Publisher: Bentham Science Publishers

ISSN (Print): 1381-6128

ISSN (Electronic): 1873-4286

Publication date (Electronic): 2023

Volume: 29

Issue: 4

Pages: 283-294

Affiliations

[1 ] deptICU , Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, , 200032, , PR China;

[2 ] deptDepartment of Functional Education and Research, Shulan International Medical College , Zhejiang Shuren University , Hangzhou, , 310015, , PR China;

[3 ] deptDepartment of Clinical Pharmacy, The First Affiliated Hospital, School of Medicine , Zhejiang University , 79 Qingchun Road, Hangzhou, , 310003, , China

Author notes

[* ]Address correspondence to these authors at the ICU, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 725 South WanPing Road, Shanghai, 200032, China; Tel: +86-021-64385700-3522; E-mail: cwdoctor@ 123456shutcm.edu.cn ; and Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, China; E-mail: ziyao1988@ 123456zju.edu.cn

[# ] These authors contributed equally to this work.

Article

Publisher ID: CPD-29-4-283

DOI: 10.2174/1381612829666230201144029

PMC ID: 10230609

PubMed ID: 36722481

SO-VID: 947b665f-cc91-4a76-8821-4ec680c6342a

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This is an Open Access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

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Arginine-Glycine-Aspartic Acid-anchored Curcumin-based Nanotherapeutics Inhibit Pyroptosis-induced Cytokine Release Syndrome for In Vivo and In Vitro Sepsis Applications

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Abstract

Aim

Background

Objective

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Results

Conclusion

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Most cited references 32

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

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