ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.
Subject(s)
Inflammation/etiology , Inflammation/metabolism , Phagocytosis/immunology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Age Factors , Aged , Animals , Apoptosis , Blister/immunology , Blister/metabolism , Blister/pathology , Cantharidin , Gene Expression , Humans , Immunity, Innate , Inflammation/pathology , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/pathology , Receptors, Cell Surface/metabolism , Signal TransductionABSTRACT
Periodontitis is an economically important disease which is highly prevalent worldwide. Current diagnostic approaches are time-consuming and require interpretation of multiple aspects of clinical and radiographic assessment. Chair-side monitoring of inflammatory mediators of periodontitis could provide immediate information about disease activity, which can inform patient management. We aimed to develop a novel prototype biosensor to measure salivary matrix metalloproteinase-8 (MMP-8) using specific antibodies and surface acoustic wave (SAW) technology. The analytical performance of the prototype biosensor was compared to standard enzyme-linked immunosorbent assay (ELISA) using unstimulated saliva samples obtained from patients with periodontitis before and after non-surgical treatment (N = 58), patients with gingivitis (N = 54) and periodontally healthy volunteers (N = 65). Receiver operator characteristic (ROC) analysis for distinguishing periodontitis from health revealed an almost identical performance between the sensor and ELISA assays (area under curve values (AUC): ELISA 0.93; SAW 0.89). Furthermore, both analytical approaches yielded readouts which distinguished between heath, gingivitis and periodontitis, correlated identically with clinical measures of periodontal disease and recorded similar post-treatment decreases in salivary MMP-8 in periodontitis. The assay time for our prototype device is 20 minutes. The prototype SAW biosensor is a novel and rapid method of monitoring periodontitis which delivers similar analytical performance to conventional laboratory assays.