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Chemokinergic and Dopaminergic Signalling Collaborates through the Heteromer Formed by CCR9 and Dopamine Receptor D5 Increasing the Migratory Speed of Effector CD4+ T-Cells to Infiltrate the Colonic Mucosa.
Campos, Javier; Osorio-Barrios, Francisco; Villanelo, Felipe; Gutierrez-Maldonado, Sebastian E; Vargas, Pablo; Pérez-Acle, Tomás; Pacheco, Rodrigo.
Afiliação
  • Campos J; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile.
  • Osorio-Barrios F; Gut Microbiology, Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 25, 3001 Bern, Switzerland.
  • Villanelo F; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile.
  • Gutierrez-Maldonado SE; Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Recoleta 8420524, Santiago, Chile.
  • Vargas P; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile.
  • Pérez-Acle T; Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Recoleta 8420524, Santiago, Chile.
  • Pacheco R; Institut Curie, PSL Research University, CNRS, UMR144, F-75005 Paris, France.
Int J Mol Sci ; 25(18)2024 Sep 18.
Article em En | MEDLINE | ID: mdl-39337509
ABSTRACT
Inflammatory bowel diseases (IBDs) involve chronic inflammation of the gastrointestinal tract, where effector CD4+ T-cells play a central role. Thereby, the recruitment of T-cells into the colonic mucosa represents a key process in IBD. We recently found that CCR9 and DRD5 might form a heteromeric complex on the T-cell surface. The increase in CCL25 production and the reduction in dopamine levels associated with colonic inflammation represent a dual signal stimulating the CCR9DRD5 heteromer, which promotes the recruitment of CD4+ T-cells into the colonic lamina propria. Here, we aimed to analyse the molecular requirements involved in the heteromer assembly as well as to determine the underlying cellular mechanisms involved in the colonic tropism given by the stimulation of the CCR9DRD5 complex. The results show that dual stimulation of the CCR9DRD5 heteromer potentiates the phosphorylation of the myosin light chain 2 (MLC2) and the migration speed in confined microchannels. Accordingly, disrupting the CCR9DRD5 assembly induced a sharp reduction in the pMLC2 in vitro, decreased the migratory speed in confined microchannels, and dampened the recruitment of CD4+ T-cells into the inflamed colonic mucosa. Furthermore, in silico analysis confirmed that the interface of interaction of CCR9DRD5 is formed by the transmembrane segments 5 and 6 from each protomer. Our findings demonstrated that the CCR9DRD5 heteromeric complex plays a fundamental role in the migration of CD4+ T-cells into the colonic mucosa upon inflammation. Thereby, the present study encourages the design of strategies for disassembling the formation of the CCR9DRD5 as a therapeutic opportunity to treat IBD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T CD4-Positivos / Transdução de Sinais / Receptores de Dopamina D5 / Receptores CCR / Mucosa Intestinal Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T CD4-Positivos / Transdução de Sinais / Receptores de Dopamina D5 / Receptores CCR / Mucosa Intestinal Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Suíça