Abstract
Acute inflammation is an immediate response to infection and injury characterised by the influx of granulocytes followed by phagocytosing mononuclear phagocytes. Provided the antigen is cleared and the immune system of the host is fully functional, the acute inflammatory response will resolve. Until now it is considered that resolution then leads back to homeostasis, the physiological state tissues experienced before inflammation occurred. Using a human model of acute inflammation driven by intradermal UV killed Escherichia coli, we found that bacteria and granulocyte clearance as well as pro-inflammatory cytokine catabolism occurred by 72h. However, following a lag phase of about 4 days there was an increase in numbers of memory T cells and CD163+ macrophage at the post-resolution site up to day 17 as well as increased biosynthesis of cyclooxygenase-derived prostanoids and DHA-derived D series resolvins. Inhibiting post-resolution prostanoids using naproxen showed that numbers of tissue memory CD4 cells were under the endogenous control of PGE2, which exerts its suppressive effects on T cell proliferation via the EP4 receptor. In addition, we re-challenged the post-resolution site with a second injection of E. coli, which when compared to saline controls resulted in primarily a macrophage-driven response with comparatively fewer PMNs; the macrophage-dominated response was reversed by cyclooxygenase inhibition. Re-challenge experiments were also carried out in mice where we obtained similar results as in humans. Therefore, we report that acute inflammatory responses in both humans and rodents do not revert back to homeostasis, but trigger a hitherto unappreciated sequence of immunological events that dictate subsequent immune response to infection.
Highlights
Following infection the acute inflammatory cascade is initiated with the specific aim of eradicating the pathogen [1]
Long before the resolution of the microvascular responses was the clearance of the UV-killed E. coli (UVkEc), which was detectable at the injection site at the peak of the acute immune response (4 h), but was largely cleared by 24 h being undetectable at 48 h, Fig 1B
Resolution of acute inflammation leads to adapted homeostasis are shown here (A)
Summary
Following infection the acute inflammatory cascade is initiated with the specific aim of eradicating the pathogen [1]. Upon successful resolution the inflamed tissue returns back to homeostasis—the cellular and biochemical state present before inflammatory challenge This view has been challenged by recent reports which show that resolution is not just the termination of innate immune response to infection/injury, but leads to cellular and biochemical events that can influence subsequent adaptive immune responses [6,7,8,9]. Some infections can cause “immunological scarring”, such that despite effective clearance of the inciting stimulus, the site becomes chronically inflamed rather than reverting to homeostasis [11,12] Taken together, these reports highlight that our current understanding of resolution should not be limited to defining it as just the end of innate immune–mediated responses to infection. We noted increased numbers of memory T cells, macrophage populations as well as robust lipid mediator biosynthesis, which we contend plays a key role in maintaining post-resolution homeostasis and mounting responses to secondary infection
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