Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing

Chambers, E. S.; Vukmanovic-Stejic, M.; Shih, B. B.; Trahir, H.; Subramanian, P.; Devine, O. P.; Glanville, J.; Gilroy, D.; Rustin, M.; Freeman, T. C.; Mabbott, N. A.; Akbar, A. N.

doi:10.1101/2020.04.02.020081

bioRxiv · 10.1101/2020.04.02.020081

Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing

Chambers, E. S.·Vukmanovic-Stejic, M.·Shih, B. B.·Trahir, H.·Subramanian, P.·Devine, O. P.·Glanville, J.·Gilroy, D.·Rustin, M.·Freeman, T. C.·Mabbott, N. A.·Akbar, A. N.

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Abstract

Ageing results in a decline in immune function. We showed previously that healthy older humans (>65 years old) have reduced antigen-specific cutaneous immunity to varicella zoster virus (VZV) antigen challenge. This was associated with p38 MAP kinase driven inflammation that was induced by mild tissue injury caused by the injection of the antigen itself. Here we show that non-specific injury induced by injection of air or saline into the skin of older adults recruits CCR2+CD14+ monocytes by CCL2 produced by senescent fibroblasts. These monocytes reduced TRM proliferation via secretion of prostaglandin E2 (PGE2). Pre-treatment with a p38-MAPK inhibitor (Losmapimod) in older adults in vivo significantly decreased CCL2 expression, recruitment of monocyte into the skin, COX2 expression and PGE2 production. This enhanced the VZV response in the skin. Therefore, local inflammation arising from interaction between senescent cells and monocytes leads to immune decline in the skin during ageing, a process that can be reversed. SummaryInflammation resulting from tissue injury blocks antigen-specific cutaneous immunity during ageing. Monocytes recruited to the skin inhibit TRM function through COX2-derived prostaglandin E2 production. Blocking inflammation and resulting prostaglandin E2 production with a p38-MAP kinase inhibitor significantly enhances cutaneous antigen-specific responses.

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Chambers, E. S., Vukmanovic-Stejic, M., Shih, B. B., Trahir, H., Subramanian, P., Devine, O. P., Glanville, J., Gilroy, D., Rustin, M., Freeman, T. C., Mabbott, N. A., Akbar, A. N.. 2020-04-03. Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing. https://doi.org/10.1101/2020.04.02.020081

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