Article

Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11cCCR2CX3CR1 counterparts, are expanded in inflammatory bowel disease

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Abstract

Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45+HLA-DR+CD14+CD64+) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11chighCCR2+CX3CR1+ cells, a phenotype also shared by circulating CD14+ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11cCCR2CX3CR1 phenotype. CD11chigh monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c Mϕ-like cells produced IL-10. CD11chigh pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14+ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11chighCCR2+CX3CR1+) into tolerogenic tissue-resident (CD11cCCR2CX3CR1) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11chigh monocyte-like cells.

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Acknowledgements

The authors kindly thank the critical input and suggestions by Dr. Elizabeth R Mann and Dr. William W Agace on this study. This work was supported by the Spanish Ministry of Economy (SAF201456642-JIN); the Instituto de Salud Carlos III (PIE13/00041, EHD16PI02); the “Asociación Española de Gastroenterología” (Becas Nuevos Investigadores 2016 and 2017) and the Community of Madrid (Consejería de Educación, Juventud y Deporte, Programa de Garantía Juvenil 2015 and 2016).

Author information

Author notes

  1. These authors contributed equally: M. Chaparro, J. P. Gisbert.

Affiliations

  1. Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain

    • D. Bernardo
    • , A. C. Marin
    • , S. Fernández-Tomé
    • , A. Montalban-Arques
    • , L. Ortega-Moreno
    • , I. Mora-Gutiérrez
    • , A. Díaz-Guerra
    • , R. Caminero-Fernández
    • , P. Miranda
    • , F. Casals
    • , M. Caldas
    • , M. Jiménez
    • , S. Casabona
    • , F. De la Morena
    • , C. Santander
    • , M. Chaparro
    •  & J. P. Gisbert
  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

    • D. Bernardo
    • , A. C. Marin
    • , A. Montalban-Arques
    • , A. Carrasco
    • , E. Tristán
    • , M. Esteve
    • , C. Santander
    • , M. Chaparro
    •  & J. P. Gisbert
  3. Department of Gastroenterology, Hospital Universitari Mútua Terrassa, Fundació Recerca Mútua Terrassa, Terrassa, Barcelona, Spain

    • A. Carrasco
    • , E. Tristán
    •  & M. Esteve
  4. Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain

    • L. Ortega-Moreno

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Contributions

D.B. was involved with study concept and design, experimental procedures, analysis and interpretation of the data and statistical analysis. I.M.G., A.C.M., A.M.A., S.F.T., A.D.G., A.C., E.T. and L.O.M. were involved with experimental procedures together with data analysis and interpretation. R.C.F., P.M., F.C., M.C., M.J., F.D.l.M., C.S., M.E., M.C. and J.P.G. performed patients identification and recruitment as well as obtention of all biological samples. D.B. and J.P.G. obtained the funds to perform this work. The manuscript was drafted by D.B. and edited by D.B., A.C.M., A.M.A., S.F.T., M.E., M.C. and J.P.G. All authors reviewed and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to D. Bernardo.

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