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NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

Cellular & Molecular Immunology volume 18, pages 1045–1057 (2021)Cite this article

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Abstract

The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case−control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

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Acknowledgements

The authors gratefully acknowledge the valuable collaboration of all the members of the Multidisciplinary Obesity Team, Clínica Universidad de Navarra, Pamplona, Spain. This work was supported by Plan Estatal I+D+I from the Spanish Instituto de Salud Carlos III–Subdirección General de Evaluación y Fomento de la investigación–FEDER (grants number PI16/01217, PI17/02183 and PI17/02188), by the Gobierno de Navarra (10/2018) and by CIBEROBN, ISCIII, Spain.

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Authors and Affiliations

  1. Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain

    Xabier Unamuno, Javier Gómez-Ambrosi, Beatriz Ramírez, Amaia Rodríguez, Sara Becerril, Gema Frühbeck & Victoria Catalán

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain

    Xabier Unamuno, Javier Gómez-Ambrosi, Beatriz Ramírez, Amaia Rodríguez, Sara Becerril, Víctor Valentí, Rafael Moncada, Camilo Silva, Javier Salvador, Gema Frühbeck & Victoria Catalán

  3. Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Javier Gómez-Ambrosi, Beatriz Ramírez, Amaia Rodríguez, Sara Becerril, Víctor Valentí, Rafael Moncada, Gema Frühbeck & Victoria Catalán

  4. Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain

    Víctor Valentí

  5. Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain

    Rafael Moncada

  6. Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain

    Camilo Silva, Javier Salvador & Gema Frühbeck

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  1. Xabier Unamuno
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Contributions

X.U. collected and analyzed data, wrote the first draft of the manuscript, contributed to discussion, and reviewed the manuscript. J.G.-A., A.R. and S.B. collected and analyzed the data, contributed to the discussion, and reviewed the manuscript. V.V., C.S., and J.S. enrolled patients, collected data, contributed to discussion, and reviewed the manuscript. B.R. and R.M. collected data, contributed to discussion, and reviewed the manuscript. G.F. designed the study, wrote the first draft of the manuscript, contributed to discussion, and reviewed the manuscript. V.C. designed the study, collected and analyzed data, wrote the first draft of the manuscript, contributed to discussion, and reviewed the manuscript. V.C. and G.F. are guarantors for the contents of the article and had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Gema Frühbeck or Victoria Catalán.

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The authors declare no competing interests.

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The study was approved, from an ethical and scientific standpoint, by the Clínica Universidad de Navarra’s Ethical Committee responsible for research, and written informed consent of participants was obtained.

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Unamuno, X., Gómez-Ambrosi, J., Ramírez, B. et al. NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling. Cell Mol Immunol 18, 1045–1057 (2021). https://doi.org/10.1038/s41423-019-0296-z

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