Trauma equals danger--damage control by the immune system

Abstract

Traumatic injuries induce a complex host response that disrupts immune system homeostasis and predisposes patients to opportunistic infections and inflammatory complications. The response to injuries varies considerably by type and severity, as well as by individual variables, such as age, sex, and genetics. These variables make studying the impact of trauma on the immune system challenging. Nevertheless, advances have been made in understanding how injuries influence immune system function as well as the immune cells and pathways involved in regulating the response to injuries. This review provides an overview of current knowledge about how traumatic injuries affect immune system phenotype and function. We discuss the current ideas that traumatic injuries induce a unique type of a response that may be triggered by a combination of endogenous danger signals, including alarmins, DAMPs, self-antigens, and cytokines. Additionally, we review and propose strategies for redirecting injury responses to help restore immune system homeostasis.

Figures

Figure 1.. Traumatic injuries induce an imbalance in immune system homeostasis.

This diagram summarizes generalized effects of injury on the immune system and the relationship to the development of SIRS and CARS phenotypes described in trauma patients. As illustrated, injury induces progressive enhancement of inflammatory and anti-inflammatory immune responses. The inflammatory response is driven by cells and mediators of the innate immune system, and the counterinflammatory response is regulated by the adaptive immune system. These opposing injury responses disrupt immune system homeostasis and lead to the development of SIRS and CARS in trauma patients. If opportunistic infections arise at time-points when there is a wide imbalance in immune homeostasis, the injured host will be at high risk of developing trauma-associated complications such as sepsis, septic shock, or MOF. Resolution of the injury response equals restoration of immune system homeostasis in patients who survive.

Figure 2.. Immune cell subsets that react to injury and control the injury response.

Tissue damage caused by trauma leads to the release of alarmins and self-antigens into extracellular compartments, which could activate macrophages (Macϕ) and Tregs. In macrophages, injury triggers a number of changes in phenotype and function, including enhanced TLR4 reactivity and antimicrobial responses, as well as increased appearance of GR-1+/CD11b+ macrophages. Tregs are then activated and have been shown to act as “master regulators” of the injury response by suppressing innate and adaptive cellular responses to trauma.