Key Points
Tissue homing Ly-6Chi monocytes express integrin α4 during systemic inflammation.
Macrophages demonstrate an immunosuppressive phenotype in the lungs.
F4/80+CD206hi macrophages express a high level of integrin αv and TGFBR1.
Visual Abstract
Abstract
Monocytes and macrophages participate in both pro- and anti-inflammatory responses during sepsis. Integrins are the cell adhesion receptors that mediate leukocyte migration and functions. To date, it is not known whether integrin profiles correlate with their trafficking, differentiation, and polarization during sepsis. In this study, using endotoxemia and cecal ligation and puncture model of murine sepsis, we have analyzed the role of surface integrins in tissue-specific infiltration, distribution of monocytes and macrophages, and their association with inflammation-induced phenotypic and functional alterations postinduction (p.i.) of sepsis. Our data show that Ly-6Chi inflammatory monocytes infiltrated into the peritoneum from blood and bone marrow within a few hours p.i. of sepsis, with differential distribution of small (Ly-6CloCD11bloF4/80lo) and large peritoneal macrophages (Ly-6CloCD11bhiF4/80hi) in both models. The results from flow cytometry studies demonstrated a higher expression of integrin α4β1 on the Ly-6Chi monocytes in different tissues, whereas macrophages in the peritoneum and lungs expressed higher levels of integrin α5β1 and αvβ3 in both models. Additionally, F4/80+ cells with CD206hiMHCIIlo phenotype increased in the lungs of both models by six hours p.i. and expressed higher levels of integrin αvβ3 in both lungs and peritoneum. The presence of such cells correlated with higher levels of IL-10 and lower levels of IL-6 and IL-1β transcripts within six hours p.i. in the lungs compared with the mesentery. Furthermore, bioinformatic analysis with its experimental validation revealed an association of integrin α4 and α5 with inflammatory (e.g., p-SRC) and integrin αv with regulatory molecules (e.g., TGFBR1) in macrophages during sepsis.
Footnotes
This work was supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India (102/IFD/SAN/1671/2014-2015 and BT/010/IYBA/2017/04) to P.P.S., a University Grants Commission, Government of India fellowship to S.P.D. (Sr. No-2061430670), and a Ministry of Human Resource Development, Government of India fellowship to P.C. (02-23-200-429).
S.P.D. and P.C. performed the experiments and analyzed the data. P.P.S. conceived and directed the study. S.P.D. and P.P.S. wrote the manuscript.
Abbreviations used in this article
- CLP
- cecal ligation and puncture
- ECM
- extracellular matrix
- LPM
- large peritoneal macrophage
- MFI
- mean fluorescence intensity
- MHCII
- MHC class II
- p.i.
- postinduction
- SPM
- small peritoneal macrophage
- STRING
- Search Tool for the Retrieval of Interacting Genes/Proteins
- Received July 14, 2020.
- Accepted September 27, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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