Abstract
The early cellular response to infection has been investigated extensively, generating valuable information regarding the mediators of acute infection response. Various cytokines have been highlighted for their critical roles, and the actions of these cytokines are related to intracellular phosphorylation changes to promote infection resolution. However, the development of chronic infections has not been thoroughly investigated. While it is known that wound healing processes are disrupted, the interactions of cytokines and phosphoproteins that contribute to this dysregulation are not well understood. To investigate these relationships, this study used a network centrality approach to assess the impact of individual cytokines and phosphoproteins during chronic inflammation and infection. Tissues were taken from patients undergoing total knee arthroplasty (TKA) and total knee revision (TKR) procedures across two tissue depths to understand which proteins are contributing most to the dysregulation observed at the joint. Notably, p-c-Jun, p-CREB, p-BAD, IL-10, IL-12p70, IL-13, and IFN-γ contributed highly to the network of proteins involved in aseptic inflammation caused by implants. Similarly, p-PTEN, IL-4, IL-10, IL-13, IFN-γ, and TNF-α appear to be central to signaling disruptions observed in septic joints. Ultimately, the network centrality approach provided insight into the altered tissue responses observed in chronic inflammation and infection.
Highlights
Acute responses to inflammation and infection have been well studied in literature, and these studies have highlighted important roles for many cytokines [1,2,3] and phosphoproteins [4,5] in early inflammatory immune processes
Less is known about the dysregulation that occurs when inflammation and infections become chronic, which is the case in localized infections like Periprosthetic joint infection (PJI) [12]
We aimed to define the impact of individual cytokines and phosphoproteins on chronic inflammation and infection in PJI using a network centrality parameter approach
Summary
Acute responses to inflammation and infection have been well studied in literature, and these studies have highlighted important roles for many cytokines [1,2,3] and phosphoproteins [4,5] in early inflammatory immune processes. The coordinated series of signaling events involves the recruitment of pro-inflammatory regulators like IL-1α, IL-1β, and IL-6 [6,7,8] to the site, provoking intracellular phosphorylation changes of many mitogen-activated protein kinase (MAPK/ERK) mediators [9,10,11]. This acute inflammatory response to infection is predictable. Less is known about the transition that leads to the development of chronic infections [12]. Dysregulation of immune mediators has been observed systemically for PJI [14,15], but the mechanisms that lead to these signaling disruptions have not been investigated [16]
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