Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

Natalia Reglero-Real; Lorena Pérez-Gutiérrez; Azumi Yoshimura; Loïc Rolas; José Garrido-Mesa; Anna Barkaway; Catherine Pickworth; Rebeca S. Saleeb; Maria Gonzalez-Nuñez; Shani N. Austin-Williams; Dianne Cooper; Laura Vázquez-Martínez; Tao Fu; Giulia De Rossi; Matthew Golding; Mathieu Benoit Voisin; Chantal M. Boulanger; Yoshiaki Kubota; William A. Muller; Sharon A. Tooze; Thomas D. Nightingale; Lucy Collinson; Mauro Perretti; Ezra Aksoy; Sussan Nourshargh

doi:10.1016/j.immuni.2021.07.012

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

Natalia Reglero-Real^*, Lorena Pérez-Gutiérrez, Azumi Yoshimura, Loïc Rolas, José Garrido-Mesa, Anna Barkaway, Catherine Pickworth, Rebeca S. Saleeb, Maria Gonzalez-Nuñez, Shani N. Austin-Williams, Dianne Cooper, Laura Vázquez-Martínez, Tao Fu, Giulia De Rossi, Matthew Golding, Mathieu Benoit Voisin, Chantal M. Boulanger, Yoshiaki Kubota, William A. Muller, Sharon A. ToozeThomas D. Nightingale, Lucy Collinson, Mauro Perretti, Ezra Aksoy, Sussan Nourshargh^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

Abstract

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

Original language	English (US)
Pages (from-to)	1989-2004.e9
Journal	Immunity
Volume	54
Issue number	9
DOIs	https://doi.org/10.1016/j.immuni.2021.07.012
State	Published - Sep 14 2021

Funding

This work was principally funded by the Wellcome Trust (098291/Z/12/Z, to S.N.). N.R.-R. is additionally supported by funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007?2013) under REA grant agreement no. 608765. The work in the labs of S.A.T. and L.C. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001187 and FC001999), the UK Medical Research Council (FC001187 and FC001999), and the Wellcome Trust (FC001187 and FC001999). E.A. was supported by the UK Medical Research Council and Barts charity grants MR/M023230/1 and MGU0488. Conceptualization and writing (original draft), N.R.-R. and S.N.; methodology, investigation, analysis, and validation, S.N. N.R.-R. L.P.G. J.G.-M. C.P. A.B. A.Y. R.S.S. M.G.-N. L.R. S.N.A.-W. L.V.-M. W.A.M. T.F. G.D.R. M.G. M.-B.V. L.C. T.D.N. and E.A.; resources, S.N. C.M.B. Y.K. W.A.M. L.C. M.P. S.A.T. T.D.N. and E.A.; editing of draft, all authors; overall project conception, supervision, and funding, S.N. The authors declare no competing interests. This work was principally funded by the Wellcome Trust ( 098291/Z/12/Z , to S.N.). N.R.-R. is additionally supported by funding from the People Programme (Marie Curie Actions) of the European Union\u2019s Seventh Framework Programme ( FP7/2007\u20132013 ) under REA grant agreement no. 608765 . The work in the labs of S.A.T. and L.C. was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001187 and FC001999 ), the UK Medical Research Council ( FC001187 and FC001999 ), and the Wellcome Trust ( FC001187 and FC001999 ). E.A. was supported by the UK Medical Research Council and Barts charity grants MR/M023230/1 and MGU0488 .

Keywords

ATG16L1
ATG5
PECAM-1
autophagy
diapedesis
endothelium
extravasation
inflammation
junctions
neutrophils

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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Reglero-Real, N., Pérez-Gutiérrez, L., Yoshimura, A., Rolas, L., Garrido-Mesa, J., Barkaway, A., Pickworth, C., Saleeb, R. S., Gonzalez-Nuñez, M., Austin-Williams, S. N., Cooper, D., Vázquez-Martínez, L., Fu, T., De Rossi, G., Golding, M., Voisin, M. B., Boulanger, C. M., Kubota, Y., Muller, W. A., ... Nourshargh, S. (2021). Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation. Immunity, 54(9), 1989-2004.e9. https://doi.org/10.1016/j.immuni.2021.07.012

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abstract = "The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.",

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Reglero-Real, N, Pérez-Gutiérrez, L, Yoshimura, A, Rolas, L, Garrido-Mesa, J, Barkaway, A, Pickworth, C, Saleeb, RS, Gonzalez-Nuñez, M, Austin-Williams, SN, Cooper, D, Vázquez-Martínez, L, Fu, T, De Rossi, G, Golding, M, Voisin, MB, Boulanger, CM, Kubota, Y, Muller, WA, Tooze, SA, Nightingale, TD, Collinson, L, Perretti, M, Aksoy, E & Nourshargh, S 2021, 'Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation', Immunity, vol. 54, no. 9, pp. 1989-2004.e9. https://doi.org/10.1016/j.immuni.2021.07.012

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AU - Reglero-Real, Natalia

AU - Pérez-Gutiérrez, Lorena

AU - Yoshimura, Azumi

AU - Rolas, Loïc

AU - Garrido-Mesa, José

AU - Barkaway, Anna

AU - Pickworth, Catherine

AU - Saleeb, Rebeca S.

AU - Gonzalez-Nuñez, Maria

AU - Austin-Williams, Shani N.

AU - Cooper, Dianne

AU - Vázquez-Martínez, Laura

AU - Fu, Tao

AU - De Rossi, Giulia

AU - Golding, Matthew

AU - Voisin, Mathieu Benoit

AU - Boulanger, Chantal M.

AU - Kubota, Yoshiaki

AU - Muller, William A.

AU - Tooze, Sharon A.

AU - Nightingale, Thomas D.

AU - Collinson, Lucy

AU - Perretti, Mauro

AU - Aksoy, Ezra

AU - Nourshargh, Sussan

PY - 2021/9/14

Y1 - 2021/9/14

N2 - The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

AB - The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

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KW - ATG5

KW - PECAM-1

KW - autophagy

KW - diapedesis

KW - endothelium

KW - extravasation

KW - inflammation

KW - junctions

KW - neutrophils

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U2 - 10.1016/j.immuni.2021.07.012

DO - 10.1016/j.immuni.2021.07.012

M3 - Article

C2 - 34363750

AN - SCOPUS:85114838767

SN - 1074-7613

VL - 54

SP - 1989-2004.e9

JO - Immunity

JF - Immunity

IS - 9

ER -

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

Abstract

Funding

Keywords

ASJC Scopus subject areas

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