The inflammation cascade is the body’s highly controlled, sequential defense against injury or infection. This fundamental protective mechanism of the innate immune system eliminates the initial cause of cell injury, clears damaged tissue, and initiates healing. While this immediate, short-term response (acute inflammation) is beneficial for survival, failure to resolve it can lead to chronic inflammation. The entire process unfolds in a structured manner, moving from initial detection to vascular changes, cell recruitment, and, finally, active resolution.
Recognizing the Threat: Immediate Triggers
The cascade begins with specialized immune sentinels, such as mast cells and resident tissue macrophages, present in the affected tissue. These cells are equipped with Pattern Recognition Receptors (PRRs) that monitor the environment for signs of danger by recognizing molecular patterns shared by many threats.
One set of patterns is Pathogen-Associated Molecular Patterns (PAMPs), molecules unique to microbes, such as lipopolysaccharide (LPS) found on Gram-negative bacteria. PRRs also detect Damage-Associated Molecular Patterns (DAMPs), molecules released from damaged or dying cells, signaling a “sterile” injury without infection.
Upon recognizing a DAMP or PAMP, sentinel cells are activated and release chemical signals, including histamine and preliminary cytokines. This initial chemical release acts as the body’s alarm system, setting the inflammatory response into motion and governing the speed and intensity of subsequent steps.
The Vascular Response: Setting the Stage
Chemical messengers released by resident immune cells immediately target the local microvasculature, specifically small arterioles and venules near the injury site. The most immediate effect is vasodilation, a widening of the blood vessels, which increases blood flow to the area. This surge of blood causes the characteristic redness (rubor) and warmth (calor).
Simultaneously, chemical signals cause endothelial cells lining the vessel walls to contract, increasing vascular permeability. This action creates small gaps, allowing fluid and plasma proteins to leak out of the bloodstream into the surrounding tissue. This fluid leakage, known as exudation, results in swelling (tumor) or edema.
The loss of plasma fluid concentrates blood cells within the vessels, slowing blood flow (stasis). This slowing prepares immune cells to exit the bloodstream. These changes in vessel architecture and flow deliver the necessary components—fluid, proteins, and cells—directly to the site of the problem.
Immune Cell Migration and Phagocytosis
With the vascular stage set, the next phase focuses on the directed movement of immune cells from the circulating blood into the injured tissue, a process called leukocyte extravasation. Chemical gradients established by early messengers, particularly chemokines, guide the immune cells toward the highest concentration of the threat, a directed movement called chemotaxis.
As blood flow slows, circulating white blood cells, primarily neutrophils, begin to move toward the vessel walls, a process known as margination. They then engage in rolling adhesion, temporarily sticking to the endothelial surface via specialized adhesion molecules. This is followed by tight adhesion, where the cells firmly lock onto the vessel wall before squeezing through the gaps (diapedesis or transmigration).
Neutrophils are the first responders, arriving within minutes to hours, and are highly effective at immediate containment and destruction. They are followed by monocytes, which differentiate into macrophages once they enter the tissue. The central function of both cell types is phagocytosis: engulfing and destroying foreign invaders, damaged cells, and cellular debris using potent enzymes. This cellular cleanup represents the peak activity of the acute inflammatory response.
Shutting Down the Response: Resolution and Repair
Inflammation is a tightly regulated, self-limiting process that must be shut down once the threat is neutralized to prevent collateral damage. The transition to resolution is driven by a lipid mediator class switch, decreasing pro-inflammatory signals and beginning the synthesis of pro-resolving mediators.
These pro-resolving molecules, Specialized Pro-resolving Mediators (SPMs), include resolvins, protectins, and maresins, synthesized from omega-3 fatty acids. SPMs halt the recruitment of new neutrophils and promote the clearance of immune cells that have completed their task.
Macrophages play a final role by engulfing dying neutrophils and other apoptotic immune cells (efferocytosis). This clearance prevents the dying cells from rupturing and releasing their toxic contents, which would otherwise prolong the inflammation. Once the area is cleared, the final stage involves tissue repair, where fibroblasts lay down new extracellular matrix to restore structure and complete healing.