Abstract
In their post-traumatic course, trauma patients suffering from multiple injuries have a high risk for immune dysregulation, which may contribute to post-injury complications and late mortality. Monocytes as specific effector cells of the innate immunity play a crucial role in inflammation. Using their Pattern Recognition Receptors (PRRs), notably Toll-Like Receptors (TLR), the monocytes recognize pathogens and/or pathogen-associated molecular patterns (PAMPs) and organize their clearance. TLR2 is the major receptor for particles of gram-positive bacteria, and initiates their phagocytosis. Here, we investigated the phagocytizing capability of monocytes in a long-term porcine severe trauma model (polytrauma, PT) with regard to their TLR2 expression. Polytrauma consisted of femur fracture, unilateral lung contusion, liver laceration, hemorrhagic shock with subsequent resuscitation and surgical fracture fixation. After induction of PT, peripheral blood was withdrawn before (-1 h) and directly after trauma (0 h), as well as 3.5 h, 5.5 h, 24 h and 72 h later. CD14+ monocytes were identified and the expression levels of H(S)LA-DR and TLR2 were investigated by flow cytometry. Additionally, the phagocytizing activity of monocytes by applying S. aureus particles labelled with pHrodo fluorescent reagent was also assessed by flow cytometry. Furthermore, blood samples from 10 healthy pigs were exposed to a TLR2-neutralizing antibody and subsequently to S. aureus particles. Using flow cytometry, phagocytizing activity was determined. P below 0.05 was considered significant. The number of CD14+ monocytes of all circulating leukocytes remained constant during the observational time period, while the percentage of CD14+H(S)LA-DR+ monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of TLR2+ expressing cells out of all monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of phagocytizing monocytes decreased immediately and remained lower during the first 3.5 h after trauma, but increased after 24 h. Antagonizing TLR2 significantly decreased the phagocytizing activity of monocytes. Both, decreased percentage of activated as well as TLR2 expressing monocytes persisted as long as the reduced phagocytosis was observed. Moreover, neutralizing TLR2 led to a reduced capability of phagocytosis as well. Therefore, we assume that reduced TLR2 expression may be responsible for the decreased phagocytizing capacity of circulating monocytes in the early post-traumatic phase.
Highlights
Induced tissue damage leads to an inflammatory response
Monocytes play a pivotal role in inflammation and show massive functional modulations in trauma patients e.g. in phagocytosis, their maturation and Toll-Like Receptors (TLR) expression or impaired cytokine secretion after ex vivo stimulation with endotoxin.[21, 37,38,39]
Porcine monocytes as demonstrated by Fairbairn et al (2013) express CD14.[40]. Fairbairn et al used another clone of the monoclonal mouse anti pig CD14 antibody (Clone: MIL2), we confirmed that the porcine model is useful for studying the in vivo function of CD14 and monocytes
Summary
Induced tissue damage leads to an inflammatory response. Inflammation itself is not detrimental but rather necessary for the resolution of injury and the healing progress. This complex process integrates and coordinates cytokines, chemokines and immune cells to deal with the damage.[1, 2] One attempt to characterize this inflammatory reaction was the concept of a trauma-induced hyper-inflammatory systemic inflammatory response syndrome (SIRS) and the counterbalancing hypo-inflammatory state (compensatory anti-inflammatory response syndrome, CARS) in the later clinical course.[1, 3] The balance between pro- and anti-inflammatory components, the SIRS-CARS paradigm, was assumed to be crucial for a successful recovery and a positive outcome.[1, 4, 5] the classification terms of SIRS and CARS are more than 20 years old, and are only of limited usefulness to describe the patient’s current immune status because they do not always correlate well with immunofunctional parameters. The injured tissue releases a large number of soluble factors that act on the endocrine, lymphoid and haematopoietic organs as well.[2]
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