Intestinal host defense outcome is dictated by PGE(2) production during efferocytosis of infected cells

Author(s):Show less -

Dejani, Naiara Naiana ^{[1, 2]} ; Orlando, Allan Botinhon ^[2] ; Nino, Victoria Eugenia ^[2] ; Penteado, Leticia de Aquino ^[2] ; Verdan, Felipe Fortino ^{[1, 2]} ; Ribeiro Bazzano, Julia Miranda ^[2] ; Codo, Ana Campos ^[2] ; Guerta Salina, Ana Carolina ^{[1, 2]} ; Saraiva, Amanda Correia ^[2] ; Avelar, Matheus Rossi ^[2] ; Spolidorio, Luis Carlos ^[3] ; Serezani, C. Henrique ^[4] ; Medeiros, Alexandra Ivo ^[2]

Affiliation

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

^[2] Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Biol Sci, BR-01049010 Araraquara, SP - Brazil

^[3] Sao Paulo State Univ, Sch Dent, Dept Physiol & Pathol, BR-01049010 Araraquara, SP - Brazil

^[4] Vanderbilt Univ, Med Ctr, Div Infect Dis, Dept Med, Nashville, TN 37232 - USA

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 115, n. 36, p. E8469-E8478, SEP 4 2018.
• Web of Science Citations: 3

Abstract

Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-beta, PGE(2), and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-beta, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic Escherichia coli-infected macrophages by dendritic cells triggers PGE(2) production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE(2) during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic E. coli-infected cells by dendritic cells promoted high levels of PGE(2), which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal Citrobacter rodentium infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against C. rodentium compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense. (AU)

• FAPESP's process: 11/17611-7 - Effect of efferocytosis by dendritic cells on Th17 differentiation: role of Prostaglandin E2
• Grantee: Alexandra Ivo de Medeiros
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 14/03967-2 - Phenotypic profile and migratory capacity of dendritic cells after apoptotic cell phagocytosis
• Grantee: Letícia de Aquino Penteado
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 12/23580-0 - Differentiation of Th17 cells during phagocytosis of infected apoptotic cells: Determination of intracellular signaling pathways via PGE2 and EP receptors
• Grantee: Naiara Naiana Dejani
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/10964-5 - Mechanism by which PGE2 originated from efferocytosis inhibits the expression of Il-1R and Th17 differentiation - Involvement of SOCS3
• Grantee: Allan Botinhon Orlando
• Support type: Scholarships in Brazil - Master