Immune response to traumatic injury: harmony and discordance of immune system homeostasis

Abstract

Trauma remains one of the leading causes of death worldwide. Traumatic injury disrupts immune system homeostasis and may predispose patients to opportunistic infections and inflammatory complications. Prevention of multiple organ dysfunction syndrome due to septic complications following severe trauma is a challenging problem. Following severe injury, the immune system usually tends toward a pro-inflammatory phenotype and then changes to a counter-inflammatory phenotype. This immune system homeostasis is believed to be a protective response based on the balance between the innate and adaptive immune systems. We reported that injury activates inflammasomes and primes Toll-like receptors. The primed innate immune system is prepared for a rapid and strong antimicrobial immune defense. However, trauma can also develop the "two-hit" response phenotype. We also reported that injury augments regulatory T cell activity, which can control the "two-hit" response phenotype in trauma. We discuss the current idea that traumatic injury induces a unique type of innate and adaptive immune response that may be triggered by damage-associated molecular pattern molecules, which are a combination of endogenous danger signal molecules that include alarmins and pathogen-associated molecular pattern molecules.

Keywords: CARS; SIRS; injury; macrophage; regulatory T cells (Tregs).

Figure 1

Immune system activation pathway following injury. The inflammasome is a large multiprotein complex that plays a key role in innate immunity by participating in the production of pro‐inflammatory cytokines such as interleukin (IL)‐1β and IL‐18. They are both produced as inactive precursors, pro‐IL‐1β and pro‐IL‐18, and share a common maturation mechanism that requires activated caspase‐1. The inflammasomes sense damage‐associated molecular patterns including pathogen‐associated molecular patterns (PAMPs) and the host‐derived signals known as alarmins. Cell death induced by inflammasome activation is known as pyroptosis. Alarmins also stimulate Toll‐like receptors (TLRs), which produce IL‐6 and tumor necrosis factor (TNF)‐α in response to injury. NF‐κB, nuclear factor‐κB.

Figure 2

Injury primes immune system. After trauma, patients are exposed to alarmins that prime the immune system to protect them from tissue injury and microbe invasion. The primed immune system could trigger excessive inflammatory cascades that may develop multiple organ failure. This excessive inflammatory cascade is called “two‐hit” response. PAMPs, pathogen‐associated molecular patterns.

Figure 3

Inflammatory responses to injury. Inflammatory responses to injury are driven predominantly by macrophages. Inflammasomes and Toll‐like receptors (TLRs) are activated by alarmins. The inflammatory responses have crucial roles in the protection of the injured host, such as clearing damaged tissue and eliminating infected microbiomes. Excessive inflammation can cause a two‐hit response.

Figure 4

Counter‐inflammatory responses to injury. Regulatory T cell activation controls Toll‐like receptor (TLR) reactivity and T helper 1 (Th1)‐type responses and T cell proliferation to protect the injured host from the two‐hit response and excessive inflammation as a main regulator. Counter‐inflammatory responses may predispose the injured host to opportunistic infections.

Figure 5

Interaction between immune cell subsets in reaction to injury. Injury‐induced tissue damage releases alarmins, which can activate macrophages and regulatory T cells (Tregs). In macrophages, injury triggers a number of changes in phenotype and function, including enhanced Toll‐like receptor 4 (TLR4) reactivity and antimicrobial responses. Regulatory T cells are activated and have been shown to act as “master regulators” of the injury response by suppressing both innate (macrophage) and adaptive (T cell) cellular responses to trauma. Th1, T helper 1.

Figure 6

Traumatic injury disrupts normal immune system homeostasis. Injury disrupts immune system homeostasis and leads to the development of systemic inflammatory response syndrome (SIRS) and compensatory anti‐inflammatory response syndrome (CARS) in trauma patients. The pro‐inflammatory response is driven by the innate immune system and the anti‐inflammatory response is regulated by the adaptive immune system. Soon after injury, inflammasomes are activated and Toll‐like receptors (TLRs) are primed predominantly in macrophages, and at the same time, regulatory T cells (Tregs) are also primed. Once a pro‐inflammatory phenotype is overexpressed, the injured host can develop the “two‐hit” response phenotype, which may lead to multiple organ dysfunction syndrome (MODS). However, if the counter‐inflammatory response is overexpressed, the injured host will be at high risk of developing trauma‐associated complications such as sepsis, septic shock, or MODS.