Inflammation can broadly be separated into three sequential phases.

Initiation

Inflammation begins with an insult or stimulus to an organ. The source of inflammation can be a foreign body, like an invading bacteria or virus, though the source of inflammation can also be damaged cells, such as necrotic cells from a physical wound, or transformed tumor cells. The initial response may differ depending on the source of inflammation. For example, TLR2, TLR4, and TLR9 can be activated by lipoproteins on the surface of bacteria and prokaryotic DNA, causing the release of cytokines (such as IL-1β, IFNα, and IFNβ) and chemokines (such as IL-8, MCP-1 and MIP-1α) promoting immune cell activation and recruitment. It is also in this stage that the complement pathway may become activated, initiating a cascade of events ultimately resulting in C3a activation enhancing inflammation and C3b, which will lead to generation of the membrane attack complex.

Elimination

At this point, C3a activation, histamine release from mast cells, and production of prostaglandin cause changes in the vasculature including vasodilation, increased blood flow, and increased vascular permeability allowing immune cells to more easily escape from blood vessels into the tissue. Immune cells, such as neutrophils and macrophages, recognize molecular patterns on the surface of invading pathogens or transformed cells and engulf these cells. The immune cells utilize cytotoxic mediators (such as reactive oxygen species) to destroy the targeted cells. Immune cells will also produce cytokines, such as TNF-α, IFN-γ, and IL-1β, which will enhance inflammation and recruit additional immune cells into the tissue.

Resolution

Dead and dying cells present “find-me” and “eat-me” signals such as phosphatidylserine, oxLDL, and sphingosine-1 phosphate, which recruit scavenging phagocytes to engulf these cells and control further inflammation. Certain cells, such as macrophages, may switch to an anti-inflammatory phenotype promoting the depletion of cytotoxic mediators through arginase-1 activity. These cells also produce anti-inflammatory cytokines such as IL-10 and TGF-β. Fibroblasts activated by TNF-α and IL-1β begin tissue remodeling and repair by laying down collagen and extracellular matrix, which can produce scar tissue. Antigen presenting cells, such as dendritic cells, process antigen from the source of injury and then travel to lymph nodes where they present the antigen to naïve T cells and B cells. Naïve T cells can differentiate into helper T cells which may propagate the immune response through release of IFN-γ and IL-2. B cells differentiate into plasma B cells, which produce antibody specific to the invading pathogen, which will more readily trigger an enhanced immune response the next time it is encountered.

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