Inflammation Overview

Inflammation is an organism’s protective response to pathogens, infection, or tissue damage and involves the coordinated communication of a variety of immune cells and blood vessels (Figure 1). The host response produces an intricate cascade of molecular signals that activate or change the actions of immune and nonimmune cells [1].

When the body detects harmful stimuli, such as bacteria, viruses, or physical injury, it triggers an inflammatory response to eliminate the cause of cell injury, clear out necrotic cells and tissues, and initiate tissue repair. Key components of this response include immune cells like neutrophils, macrophages, dendritic cells, T cells, and B cells, as well as blood vessels that undergo vasodilation and increased permeability to facilitate the movement of immune cells and proteins to the affected area. While inflammation is essential for protection and healing, excessive or prolonged inflammation can lead to tissue damage and contribute to chronic diseases.

This overview discusses the general phenomenon of inflammation and triggers to the process.

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Physiological and pathological inflammation is an adaptive response that plays a critical role in host defense against infection and disease occurring in response to tissue damage from microbial pathogen, infection, chemical irritation, and other trauma. Inflammation may be acute or chronic in duration. Acute inflammation is a short-term response that occurs as the body works to heal itself by resolving an infection or tissue injury. Depending on the amount of damage, the acute phase may be enough to resolve the problem. Conversely, chronic inflammation is a prolonged response that can cause continuous damage to tissues and organs. It can be harmful and is linked to serious diseases. 

An inflammatory response is the activation of the immune system to eliminate pathogens or damaged cells. This response includes the release of signaling molecules like cytokines and chemokines, and the recruitment of immune cells such as neutrophils and macrophages to the site of injury or infection (Figure 1). Critical cell signaling pathways, such as the NF-κB and MAPK pathways, play a significant role in regulating the production and release of these inflammatory mediators. While inflammation is essential for protecting the body and promoting healing, dysregulated or chronic inflammation can contribute to various diseases, including autoimmune disorders, cardiovascular diseases, and cancer.

Cell signaling pathways are triggered by nucleic acids, proteins, and sugars from pathogens or damaged cells (Figure 2). Some of these triggers are recognized as common molecules and conserved structural patterns and bind to a specific set of pattern recognition receptors (PRRs) found on immune cells [2].

When a pathogen breaches the skin or mucus membrane, cells of the innate immune system mount an immediate response.  To initiate this response, the immune system recognizes pathogen associated molecular patterns (PAMPs) from bacteria and viruses [3].  PAMPs include bacterial and viral nucleic acids and other conserved molecules (Table 1). PAMPs bind several families of surface and intracellular PRRs on immune cells. PRR signaling uses several receptors including Toll like receptors and NLRs (nucleotide-binding, oligomerization domain (NOD)-like receptors), and c-type lectin (receptor for advanced glycation end-products).

The immune system has a set of sensors that detect molecules related to tissue damage known as damage associated molecular patterns (DAMPs).  The immune system triggers DAMPs as a response to cell death during infection from a microbe or toxin. DAMPs can be activated under sterile conditions to have immune cells eliminate dying cells. Once activated, PRRs initiate a signaling cascade that results in an inflammatory response.  Common DAMPs include heat shock proteins (HSP), HMGB-1, uric acid, and extracellular ATP (Table 1) [4, 5].  DAMPs can bind receptors including advanced glycation end products (RAGE), triggering receptors expressed on myeloid cells (TREMs), and ion channels (Figure 2).
 

Learn more: Cell Signaling Pathways
Learn more: Pattern Recognition Receptors Overview

The presence of inflammation is indicated by populations of activated immune cells and cytokines. There are multiple inducers for the inflammatory process that can be used on immune cells from blood or tissue samples and directly in animal models.

Endotoxins including LPS are potent, short-lived inducers for inflammation. LPS is used as an agent both in vivo and in vitro to understand molecular pathways and model the immune response [3, 4, 5]. Applying LPS to PBMCs can activate and induce production of cytokines secreted by a wide range of immune cells (Figure 3) [4]. LPS can be applied in a dose and time dependent manner to modulate the inflammatory response. 

Animal LPS challenge models are used in drug discovery to characterize anti-inflammatory therapeutics. LPS administered to animals via intravenously or intradermally allows for systemic or local inflammatory responses [5]. As in cell culture models, the inflammatory response can be modulated based on LPS dose and time. Blood or serum can be analyzed for secreted cytokines.
 

Activating inflammation in the CNS and brain is challenging as it is protected by the blood-brain barrier. Mouse models are often used to overexpress inflammatory agents including β amyloid [9]. LPS can be used as a challenge model to induce neuronal damage and activate inflammation [10]. Microglial cells (Table 2), a type of tissue resident macrophage (Figure 4) are stimulated and recruited to the area of injury. Serum from harvested brain samples can be measured for neural specific injury markers including GFAP, S100B, NF-H, and UCH-L1.

Learn more: Stimulation of Cytokine Production in Immune Cells Protocol
Learn more: Immune Cell Stimulation via LPS Protocol