Leukotriene B-4 licenses inflammasome activation to enhance skin host defense

Author(s):Show less -

Guerta Salina, Ana Carolina ^{[1, 2, 3]} ; Brandt, Stephanie L. ^{[4, 2]} ; Klopfenstein, Nathan ^{[2, 5]} ; Blackman, Amondrea ^[2] ; Ribeiro Bazzano, Julia Miranda ^[2] ; Sa-Nunes, Anderson ^{[6, 2]} ; Byers-Glosson, Nicole ^[4] ; Brodskyn, Claudia ^[7] ; Tavares, Natalia Machado ^[7] ; Santos Da Silva, Icaro Bonyek ^[7] ; Medeiros, I, Alexandra ; Henrique Serezani, C. ^{[2, 5, 8, 9]}

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Vanderbilt Univ, Dept Med, Div Infect Dis, Med Ctr, Nashville, TN 37232 - USA

^[3] I, Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Biol Sci, BR-14800903 Araraquara, SP - Brazil

^[4] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 - USA

^[5] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Infect Immunol & Inflammat, Nashville, TN 37232 - USA

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 Sao Paulo, SP - Brazil

^[7] Fiocruz MS, Goncalo Moniz Inst, Oswaldo Cruz Fdn, BR-40296710 Salvador, BA - Brazil

^[8] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 - USA

^[9] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Immunobiol, Nashville, TN 37232 - USA

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 117, n. 48, p. 30619-30627, DEC 1 2020.
• Web of Science Citations: 0

Abstract

The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1 beta and IL-18 in addition to inducing a type of inflammatory cell death termed ``pyroptosis.{''} Leukotriene B-4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1 beta and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB4-mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1 beta-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense. (AU)

• FAPESP's process: 17/19870-6 - Effect of phagocytosis of infected apoptotic cells during activation of M1/M2 Macrophages
• Grantee: Alexandra Ivo de Medeiros
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/04786-0 - Activation of M1/M2 Macrophages by efferocytosis of infected apoptotic cells
• Grantee: Ana Carolina Guerta Salina
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/10839-4 - Deciphering Aedes aegypti-vertebrate host interactions at skin level by imaging mass spectrometry
• Grantee: Anderson de Sá Nunes
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 18/01622-9 - LTB4 actions in infected apoptotic cells clearance during Staphylococcus aureus skin infection in diabetic mice.
• Grantee: Ana Carolina Guerta Salina
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate