Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll -like receptors 2 and 4

Author(s)

Moraes-Vieira, Pedro M. ^{[1, 2, 3, 4]} ; Yore, Mark M. ^{[1, 2, 5]} ; Sontheimer-Phelps, Alexandra ^{[1, 2, 6]} ; Castoldi, Angela ^{[1, 2]} ; Norseen, Julie ^{[1, 2]} ; Aryal, Pratik ^{[1, 2]} ; Sjoedin, Kotryna Simonyte ^{[1, 2, 7]} ; Kahn, Barbara B. ^{[1, 2]}

Affiliation

^[1] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Boston, MA 02215 - USA

^[2] Harvard Med Sch, Boston, MA 02215 - USA

^[3] Univ Estadual Campinas, Dept Genet Evolut Microbiol & Immunol, Obes & Comorbid Res Ctr, Lab Immunometab, Inst Biol, BR-13083862 Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Div Metab, Expt Med Res Cluster, BR-13083862 Campinas, SP - Brazil

^[5] Jounce Therapeut Inc, Cambridge, MA 02139 - USA

^[6] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02215 - USA

^[7] Umea Univ, Dept Clin Sci, Pediat, S-90187 Umea - Sweden

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 117, n. 49, p. 31309-31318, DEC 8 2020.
• Web of Science Citations: 0

Abstract

Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1 beta (IL1 beta) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1 beta is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4-overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1 beta. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1 beta levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NLRP3-inflammasome priming. These studies may provide approaches to reduce AT inflammation and insulin resistance in obesity and diabetes. (AU)

• FAPESP's process: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/02218-6 - A study of the signaling pathways induced by RBP4 in macrophages and dendritic cells in obesity-induced insulin resistance
• Grantee: Angela Castoldi
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate