Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

Karen T. Feehan; Hannah Bridgewater; Jan Stenkiewicz-Witeska; Roel P. H. De Maeyer; John Ferguson; Matthias Mack; Jeremy Brown; Giuseppe Ercoli; Connar M. Mawer; Arne Akbar; James R. W. Glanville; Parinaaz Jalali; Olivia V.  Bracken; Anna Nicolaou; Alexandra C.  Kendall; Michelle A.  Sugimoto; Derek W. Gilroy

doi:10.1038/s41467-024-48138-y

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

Karen T. Feehan, Hannah Bridgewater, Jan Stenkiewicz-Witeska, Roel P. H. De Maeyer, John Ferguson, Matthias Mack, Jeremy Brown, Giuseppe Ercoli, Connar M. Mawer, Arne Akbar, James R. W. Glanville, Parinaaz Jalali, Olivia V. Bracken, Anna Nicolaou, Alexandra C. Kendall, Michelle A. Sugimoto, Derek W. Gilroy

Centre for Health and Life Sciences

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

9 Citations (Scopus)

17 Downloads (Pure)

Abstract

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE ₂) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4 ⁺/CD44 ⁺/CD62L ⁺ and CD4 ⁺/CD44 ⁺/CD62L ^-/CD27 ⁺ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE ₂ signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation.

Original language	English
Article number	4326
Number of pages	17
Journal	Nature Communications
Volume	15
Early online date	21 May 2024
DOIs	https://doi.org/10.1038/s41467-024-48138-y
Publication status	E-pub ahead of print - 21 May 2024

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
©The Author(s) 2024

Funder

The authors wish to acknowledge the financial support provided by a BBSRC-AstraZeneca/CASE studentship. We also wish to thank Neil O’Hara (University of Manchester) for excellent technical support. The authors also wish to acknowledge the expertise and technical guidance of the Digital Pathology Omics (DPOC), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. University of Oxford.

Funding

The authors wish to acknowledge the financial support provided by a BBSRC-AstraZeneca/CASE studentship. We also wish to thank Neil O’Hara (University of Manchester) for excellent technical support. The authors also wish to acknowledge the expertise and technical guidance of the Digital Pathology Omics (DPOC), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. University of Oxford.

Keywords

Acute inflammation
Bacterial infection
Lipid signalling
CD4-positive T cells

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1038/s41467-024-48138-yLicence: CC BY

Bridgewater2024VoRFinal published version, 7.02 MBLicence: CC BY

Cite this

Feehan, K. T., Bridgewater, H., Stenkiewicz-Witeska, J., De Maeyer, R. P. H., Ferguson, J., Mack, M., Brown, J., Ercoli, G., Mawer, C. M., Akbar, A., Glanville, J. R. W., Jalali, P., Bracken, O. V., Nicolaou, A., Kendall, A. C., Sugimoto, M. A., & Gilroy, D. W. (2024). Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia. Nature Communications, 15, Article 4326. Advance online publication. https://doi.org/10.1038/s41467-024-48138-y

Feehan, KT, Bridgewater, H, Stenkiewicz-Witeska, J, De Maeyer, RPH, Ferguson, J, Mack, M, Brown, J, Ercoli, G, Mawer, CM, Akbar, A, Glanville, JRW, Jalali, P, Bracken, OV, Nicolaou, A, Kendall, AC, Sugimoto, MA & Gilroy, DW 2024, 'Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia', Nature Communications, vol. 15, 4326. https://doi.org/10.1038/s41467-024-48138-y

@article{5374981ca4ac454d8aed1bbc7db03fc0,

title = "Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia",

abstract = "Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE 2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4 +/CD44 +/CD62L + and CD4 +/CD44 +/CD62L -/CD27 + T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE 2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation.",

keywords = "Acute inflammation, Bacterial infection, Lipid signalling, CD4-positive T cells",

author = "Feehan, \{Karen T.\} and Hannah Bridgewater and Jan Stenkiewicz-Witeska and \{De Maeyer\}, \{Roel P. H.\} and John Ferguson and Matthias Mack and Jeremy Brown and Giuseppe Ercoli and Mawer, \{Connar M.\} and Arne Akbar and Glanville, \{James R. W.\} and Parinaaz Jalali and Bracken, \{Olivia V.\} and Anna Nicolaou and Kendall, \{Alexandra C.\} and Sugimoto, \{Michelle A.\} and Gilroy, \{Derek W.\}",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. {\textcopyright}The Author(s) 2024",

year = "2024",

month = may,

day = "21",

doi = "10.1038/s41467-024-48138-y",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

AU - Feehan, Karen T.

AU - Bridgewater, Hannah

AU - Stenkiewicz-Witeska, Jan

AU - De Maeyer, Roel P. H.

AU - Ferguson, John

AU - Mack, Matthias

AU - Brown, Jeremy

AU - Ercoli, Giuseppe

AU - Mawer, Connar M.

AU - Akbar, Arne

AU - Glanville, James R. W.

AU - Jalali, Parinaaz

AU - Bracken, Olivia V.

AU - Nicolaou, Anna

AU - Kendall, Alexandra C.

AU - Sugimoto, Michelle A.

AU - Gilroy, Derek W.

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. ©The Author(s) 2024

PY - 2024/5/21

Y1 - 2024/5/21

N2 - Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE 2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4 +/CD44 +/CD62L + and CD4 +/CD44 +/CD62L -/CD27 + T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE 2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation.

AB - Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE 2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4 +/CD44 +/CD62L + and CD4 +/CD44 +/CD62L -/CD27 + T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE 2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation.

KW - Acute inflammation

KW - Bacterial infection

KW - Lipid signalling

KW - CD4-positive T cells

UR - https://www.scopus.com/pages/publications/85193691774

U2 - 10.1038/s41467-024-48138-y

DO - 10.1038/s41467-024-48138-y

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 4326

ER -

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

Abstract

Bibliographical note

Funder

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this