The role of macrophages in thermal injury

Abstract

Macrophages, first discovered for their phagocytic ability, are a complicated and heterogeneous cell type. The unique properties of macrophages allow them to perform a vast array of functions, including phagocytosis, cytokine production, antigen presentation, and wound healing. Some macrophage populations are derived from monocytes and are induced into specific phenotypes by the local tissue microenvironment, while other macrophages form during early embryonic development. The exposure of the host to local pathogens and/or traumatic injury alters the tissue microenvironment and, in turn, influences changes in macrophage phenotype and function. Perhaps the most significant change in the local tissue microenvironment and subsequent macrophage phenotype occurs after thermal injury, which causes localized tissue damage and a massive systemic inflammatory response. However, few studies have explored the influence of burn injury on the host macrophages and macrophage function in burn wounds. Furthermore, the literature is scant regarding the impact macrophage function has on outcomes in thermal injury. This review will focus on the current knowledge of macrophage function in burn wounds and the phenotypic changes in macrophages during thermal injury while identifying knowledge gaps.

Keywords: Macrophages; macrophage dysfunction; macrophage phenotype; thermal injury; wound healing.

Figure 1

Development of tissue-resident macrophages. Macrophages can be derived from early embryonic development (the fetal liver or yolk sac) or from monocytes. Circulating monocytes develop from hematopoietic cells in the bone marrow and are induced into their specific phenotypes by the local tissue microenvironment.

Figure 2

Three phases of wound healing after thermal injury. The wound healing cascade is described by three interrelated and overlapping phases: inflammation (red), proliferation (green), and remodeling (blue). Inflammation begins immediately upon burn injury and can last approximately 5-7 days. Proliferation covers 3-10 days post-injury, while remodeling can take up to a year to complete after injury. While macrophages are implicated in all aspects of the wound healing process, macrophage dysfunction can lead to severe complications such as sepsis or death or cosmetic complications such as hypertrophic scarring and contractures.

Figure 3

Macrophage polarization and function. Monocyte-derived macrophages can differentiate into activated macrophages (M1) or alternatively activated macrophages (M2) depending on environmental signals. Interferon (IFN) and lipopolysaccharide (LPS) are common stimulators of M1 polarization. M2 macrophages are further divided into four subgroups that are differentially activated: M2a is stimulated by interleukin (IL)-4 or IL-13; M2b by IL-1 or toll-like receptor (TLR) agonists; M2c by glucocorticoids (GC) or IL-10; and M2d by TLR agonists through the adenosine receptor (AR). Classically activated macrophages are associated with pro-inflammation and microbicidal activity and appear immediately after tissue injury. However, persistence can block appropriate wound healing. Conversely, alternatively activated macrophages appear at later time points and are associated with anti-inflammation and tissue remodeling as part of the wound healing process.