The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair

Abstract

Objective: To discuss the acute phase of inflammatory response with a focus on the neutrophilic response and its role in inflammation. We discuss the relative balance between the need for inflammation to stimulate repair and the need to limit inflammation because of the additional damage it causes.

Data sources: We conducted a MEDLINE search from 1966 to 2005 for literature related to acute inflammation, muscle injury, and repair using combinations of the key words inflammation, neutrophil, macrophage, and cytokines. Additional literature was acquired through cross-referencing of bibliographies of articles obtained through the MEDLINE searches.

Data synthesis: We reviewed more than 200 relevant articles. Although neutrophils are an important cell population in acute inflammation, few athletic trainers are familiar with the neutrophil's actions or its dichotomous role as both perpetrator of tissue damage and initiator of repair. Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage by macrophages. These actions are orchestrated by numerous cytokines and the expression of their receptors, which represent a potential means for inhibiting selective aspects of inflammation.

Conclusions: Neutrophils infiltrate injured tissues but can also be present after noninjurious exercise. These cells have both specific and nonspecific defensive immune system functions that can cause tissue damage in isolation or as sequelae to other tissue injury. It might seem that limiting the action of neutrophils would be clinically beneficial, but these cells are also responsible for initiating the reparative process that is later managed by macrophages. Although achieving a therapeutic balance between limiting inflammation and stimulating repair is important, the duplicitous roles of neutrophils and macrophages in both the inflammation and healing processes create a physiologic paradox for clinicians whose goals are to limit inflammation and to stimulate healing after acute soft tissue injury.

Figure 1. Modified muscle use may result in an increased intracellular calcium concentration, resulting in an increased cell production of proinflammatory cytokines such as TNF-α and IL-1β, which in turn upregulate the expression of endothelial-leukocyte adhesion molecules (E-selectin and P-selectin). The activated endothelium attracts neutrophils to the region and also releases the neutrophil chemoattractants and proinflammatory cytokines IL-6 and IL-8. IL-6 indicates interleukin 6; IL-8, interleukin 8; IL-1β, interleukin 1-beta; TNF-α, tumor necrosis factor–alpha; 1β; TNF-α, tumor necrosis factor–α; and ECM, extracellular matrix.

Figure 2. Rabbit tibialis anterior muscles were subjected to an injurious eccentric exercise protocol after 1 of 3 treatments. *Note the significant reduction ( P < .01) in torn fibers postexercise in the M1/70 group (blocked respiratory burst from neutrophils) compared with the 2 control groups exposed to saline and immunoglobulin G (IgG), with intact neutrophil function and burst not blocked. Used with permission from the American Physiological Society. .

Figure 3. Schematic illustration demonstrating the proposed role of the stretch-activated calcium channels (SACs) and neutrophil recruitment in the inflammatory response of skeletal muscle. Solid lines represent initial events in muscle inflammation, and dotted lines denote the proinflammatory signaling cascade that results. Hypothetically, modified skeletal muscle use results in an increased intracellular calcium concentration. This starts a cascade of cell signaling, endothelial activation, and white blood cell recruitment, the magnitude of which may be stress or strain dependent. ROS indicates reactive oxygen species; ECM, extracellular matrix.