Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging

Emma S Chambers; Milica Vukmanovic-Stejic; Barbara Shih; Hugh  Trahair; Priya Subramanian; Oliver P.  Devine; James  Glanville; Derek W. Gilroy; Malcolm Rustin; Thomas C Freeman; Neil Mabbott; Arne N Akbar

doi:10.1038/s43587-020-00010-6

Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging

Emma S Chambers, Milica Vukmanovic-Stejic, Barbara Shih, Hugh Trahair, Priya Subramanian , Oliver P. Devine , James Glanville , Derek W. Gilroy, Malcolm Rustin , Thomas C Freeman, Neil Mabbott, Arne N Akbar

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Abstract / Description of output

We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a non specific inflammatory response to the injection itself.
Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2 (PGE2) that inhibited resident memory T cell (TRM) activation and proliferation. Pre-treatment of older subjects with a p38-MAPK inhibitor in vivo decreased CCL2 expression and inhibited monocyte recruitment and secretion of PGE2. This coincided with an increased response to VZV antigen challenge in the skin. Our results point to a series of molecular and cellular mechanisms that link cellularsenescence, tissue damage, excessive inflammation and reduced immune responsiveness
in human skin and demonstrate that tissue-specific immunity can be restored in older adults by the short-term inhibition of inflammatory responses.

Original language	English
Journal	Nature Aging
DOIs	https://doi.org/10.1038/s43587-020-00010-6
Publication status	Published - 14 Jan 2021

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Chambers-NatAging-AcceptedAccepted author manuscript, 3.08 MBLicence: Creative Commons: Attribution (CC-BY)

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Chambers, E. S., Vukmanovic-Stejic, M., Shih, B., Trahair, H., Subramanian , P., Devine , O. P., Glanville , J., Gilroy, D. W., Rustin , M., Freeman, T. C., Mabbott, N., & Akbar, A. N. (2021). Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nature Aging. https://doi.org/10.1038/s43587-020-00010-6

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title = "Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging",

abstract = "We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a non specific inflammatory response to the injection itself.Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2 (PGE2) that inhibited resident memory T cell (TRM) activation and proliferation. Pre-treatment of older subjects with a p38-MAPK inhibitor in vivo decreased CCL2 expression and inhibited monocyte recruitment and secretion of PGE2. This coincided with an increased response to VZV antigen challenge in the skin. Our results point to a series of molecular and cellular mechanisms that link cellularsenescence, tissue damage, excessive inflammation and reduced immune responsivenessin human skin and demonstrate that tissue-specific immunity can be restored in older adults by the short-term inhibition of inflammatory responses.",

author = "Chambers, {Emma S} and Milica Vukmanovic-Stejic and Barbara Shih and Hugh Trahair and Priya Subramanian and Devine, {Oliver P.} and James Glanville and Gilroy, {Derek W.} and Malcolm Rustin and Freeman, {Thomas C} and Neil Mabbott and Akbar, {Arne N}",

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doi = "10.1038/s43587-020-00010-6",

language = "English",

journal = "Nature Aging",

issn = "2662-8465",

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T1 - Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging

AU - Chambers, Emma S

AU - Vukmanovic-Stejic, Milica

AU - Shih, Barbara

AU - Trahair, Hugh

AU - Subramanian , Priya

AU - Devine , Oliver P.

AU - Glanville , James

AU - Gilroy, Derek W.

AU - Rustin , Malcolm

AU - Freeman, Thomas C

AU - Mabbott, Neil

AU - Akbar, Arne N

PY - 2021/1/14

Y1 - 2021/1/14

N2 - We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a non specific inflammatory response to the injection itself.Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2 (PGE2) that inhibited resident memory T cell (TRM) activation and proliferation. Pre-treatment of older subjects with a p38-MAPK inhibitor in vivo decreased CCL2 expression and inhibited monocyte recruitment and secretion of PGE2. This coincided with an increased response to VZV antigen challenge in the skin. Our results point to a series of molecular and cellular mechanisms that link cellularsenescence, tissue damage, excessive inflammation and reduced immune responsivenessin human skin and demonstrate that tissue-specific immunity can be restored in older adults by the short-term inhibition of inflammatory responses.

AB - We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a non specific inflammatory response to the injection itself.Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2 (PGE2) that inhibited resident memory T cell (TRM) activation and proliferation. Pre-treatment of older subjects with a p38-MAPK inhibitor in vivo decreased CCL2 expression and inhibited monocyte recruitment and secretion of PGE2. This coincided with an increased response to VZV antigen challenge in the skin. Our results point to a series of molecular and cellular mechanisms that link cellularsenescence, tissue damage, excessive inflammation and reduced immune responsivenessin human skin and demonstrate that tissue-specific immunity can be restored in older adults by the short-term inhibition of inflammatory responses.

U2 - 10.1038/s43587-020-00010-6

DO - 10.1038/s43587-020-00010-6

M3 - Article

SN - 2662-8465

JO - Nature Aging

JF - Nature Aging

ER -

Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging

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