What is the inflammatory response?
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. .
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 occurs as the body works to heal itself by resolving of infection or tissue injury. Depending on the amount of damage, the acute phase may be enough to resolve the problem. Conversely, chronic inflammation can be harmful and is linked to serious diseases.
This page discusses the general phenomenon of inflammation and triggers to the process.
Figure 1. The inflammatory response. Multiple cell types including granulocytes, NK cells, monocytes, macrophages, T cells and B cells are required for removal of damaged cells or pathogens. Inflammatory inducers, including infection or tissue damage, set off a cascade of cytokines, chemokines, and other proteins to help signal immune cells.
What activates inflammation?
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 .
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 . 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).
Table 1. Nonexclusive list of PAMPs and DAMPs that trigger inflammation.
|PAMP examples||DAMP examples|
|Microbial nucleic acids||Mitochondrial DNA (mtDNA)|
|Unmethylated CpG motifs||Uric acid|
|Double stranded RNA||S100 proteins|
|Single stranded RNA||Heat shock proteins|
|Lipoteichoic acid||β amyloid (Aβ)|
|Lipopolysaccharide (LPS)||Advanced glycation end products (AGEs)|
Figure 2. Activators to the early stages of inflammation.
Pattern recognition receptors (PRRs) include pathogen and damaged associated molecular patterns (PAMPs and DAMPs). Receptors on innate immune cells recognize inflammation inducers and will activate the immune response.
How to activate inflammation in model systems
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) . 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 . 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.
Figure 3. Inflammation induced by LPS measured by Human 65plex ProCartaPlex Assay. Human PBMCs were stimulated with 10 μg/mL LPS for 24 (d1), 48, and 72 h (d3). Cell culture supernatant was probed for the following 65 markers with Invitrogen ProcartaPlex Human 65-plex panel (Thermo Fisher Scientific Cat. No. EPX650-10065-901) kit: APRIL, BAFF, BLC, CD30, CD40L, ENA-78, Eotaxin, Eotaxin-2, Eotaxin-3, FGF-2, Fractalkine, G-CSF, GM-CSF, GROα, HGF, IFN-α, IFN-ɣ, IL-1α, IL-1β, IL-2, IL-2R, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-18, IL-20, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, I-TAC, LIF, MCP-1, MCP-2, MCP-3, M-CSF, MDC, MIF, MIG, MIP-1α, MIP-1β, MIP-3α, MMP-1, NGF-β, SCF, SDF-1α, TNF-α, TNF-β, TNF-R2, TRAIL, TSLP, TWEAK, and VEGF-A.
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 . LPS can be used as a challenge model to induce neuronal damage and activate inflammation . 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.
Table 2. Nonexclusive list for tissue resident microglial cells.
|Species||Marker type||Marker||Clone (flow cytometry)||Location|
Figure 4. Microglial cells in brain tissue.
Immunohistochemistry of paraffin-embedded human brain tissue slide using 27585-1-AP (TMEM119 antibody) at dilution of 1:1000 (under 40x lens) heat mediated antigen retrieved with Tris-EDTA buffer (pH 9).
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