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

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.

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

“…Previous papers that have discussed COVID-19 in the context of aging and immunesenescence have speculated that inflammaging would predispose the older adult to severe infection by fuelling an exaggerated pro-inflammatory response to SARS-CoV-2 ( 202 , 203 ). However, based on emerging data that suggests excessive pro-inflammatory responses in older adults negatively regulates their immune responses ( 204 , 205 ), we propose the following alternative hypothesis: inflammaging predisposes older adults to severe COVID-19 by suppressing the immune response to SARS-CoV-2 . Whilst in vitro and in vivo studies have demonstrated that exposure to pro-inflammatory cytokines can modulate the phenotype and/or function of innate and adaptive immune cells ( 147 – 149 , 206 ), it is the work of Akbar et al that have specifically linked hyper-inflammation to impaired antigen specific immune responses during aging.…”

“…Whilst in vitro and in vivo studies have demonstrated that exposure to pro-inflammatory cytokines can modulate the phenotype and/or function of innate and adaptive immune cells ( 147 – 149 , 206 ), it is the work of Akbar et al that have specifically linked hyper-inflammation to impaired antigen specific immune responses during aging. Using a human experimental system that investigates antigen-specific immunity in vivo , the group has consistently demonstrated an age-related impairment in the delayed type hypersensitivity (DTH) response to varicella zoster virus (VSV) antigen ( 204 , 205 , 207 ). Attributed to aberrant activation of P38 MAPK signaling, the decreased VZV antigen responsiveness of older adults is associated with an accumulation of CCR2 + monocytes that inhibit T cell proliferation via the production of prostaglandin E2 (PGE 2 ) ( 204 , 205 ).…”

“…Using a human experimental system that investigates antigen-specific immunity in vivo , the group has consistently demonstrated an age-related impairment in the delayed type hypersensitivity (DTH) response to varicella zoster virus (VSV) antigen ( 204 , 205 , 207 ). Attributed to aberrant activation of P38 MAPK signaling, the decreased VZV antigen responsiveness of older adults is associated with an accumulation of CCR2 + monocytes that inhibit T cell proliferation via the production of prostaglandin E2 (PGE 2 ) ( 204 , 205 ).…”

“…However, it is interesting that metatranscriptomic sequencing of BALF from COVID-19 patients aged 40-61 years detected an up-regulation of CCL2 ( 212 ), a chemokine produced in large amounts by senescent cells ( 213 , 214 ). Moreover, CCL2 is the chemoattractant for CD14 ++ CCR2 + classical and intermediate monocytes, which in the abovementioned VZV models were more abundant at sites of antigenic challenge in older adults and negatively regulated the adaptive immune response ( 204 ). Thus, in response to SARS-CoV-2, the pulmonary immune response of older adults may share features reminiscent of the impaired cutaneous immune response described in DTH models, in that, via the CCL2-mediated recruitment of PGE 2 -secreting monocytes, a hyper-inflammatory response would impede T cell function.…”

“…Since vimentin was recently found to be expressed on the surface of senescent lung fibroblasts ( 221 ), and the fact that SARS-CoV-1 and SARS-CoV-2 utilize the same mechanism of attachment to host cells, a number of groups have proposed increased SARS-CoV-2 replication would occur in individuals with a high senescent cell burden ( 222 – 224 ). Thus, an increased presence of senescent cells may predispose to the development of severe COVID-19 via two mechanisms: ( 1 ) reduced immune cell clearance by contributing to the aforementioned inflammation-induced suppression of innate and adaptive immunity ( 204 , 205 , 225 ) and ( 3 ) increasing viral load by acting as a site of enhanced SARS-CoV-2 replication. Interestingly, a number of clinical trials assessing the therapeutic benefit of drugs that directly eliminate senescent cells or suppress their SASP are already underway in patients with COVID-19 ( 223 , 226 ).…”