Innate Immunity II

Inflammation is the body's response to harmful stimuli, such as pathogens or damaged cells (The pillars of inflammation).

Two types of Pattern Recognition Receptors (PRR) are involved in the detection of harmful stimuli: Toll-like receptors (TLR) and NOD-like receptors (NLR).

NLRs are intracellular receptors that detect degraded products from phagocytosed pathogens. They include NOD1 and NOD2.

NOD1 recognizes the degraded peptidoglycan of Gram-negative bacteria, while NOD2 recognizes the degraded peptidoglycan of many bacteria.

NOD receptors have a CARD (caspase-recruitment domain) at their terminal end, which allows binding to the CARD on the ends of RIPK2 (receptor interacting serine/threonine kinase 2).

When NOD binds to its ligand, it dimerizes and RIPK2 binds, leading to the phosphorylation and activation of TAK1 (transforming growth factor beta-activated kinase 1).

Activated TAK1 then phosphorylates and activates IKK (Iκβ kinase). IKK degrades Iκβ, which is bound to NF-κB (nuclear factor-kappa B).

NF-κB translocates to the nucleus and induces cytokine production, phagocytosis and defensin synthesis.

RIG-I-like receptors (RLR) are cytoplasmic detection proteins for viral RNA.

RLRs consist of RIG-I and MDA-5, which bind to viral RNA and through CARDs interact with MAVS (mitochondrial antiviral signaling proteins).

Resulting in the phosphorylation of IRF3 (interferon response factor 3), which dimerizes and becomes a transcription factor for type I interferons (IFNs).

Type I IFN signaling induces the interferon response, which prevents viral protein synthesis and production of new virions.

Early responder cells such as neutrophils infiltrate the site of inflammation through selectin and integrin interactions.

Selectins on the surface of vascular endothelial cells are induced by IL-1 and TNF-α, allowing immune cells to roll along the vascular surface.

Integrins on the surface of neutrophils interact with vascular endothelia to firmly adhere the neutrophils to the blood vessel surface.

Neutrophils produce CXCL8 (IL-8) in response to the presence of pathogens, which attracts more neutrophils to the site of inflammation.

Chemokines increase integrin binding and selectin interactions, allowing neutrophils to move through the endothelial cell layer and penetrate the extracellular matrix (diapedesis).

Macrophages also play a role in inflammation by producing chemokines that attract neutrophils to the site of infection.

TNF-α weakens tight junctions and neutrophil proteases loosen PECAM-1 interactions, allowing neutrophils to slide through the endothelial cell layer and penetrate the extracellular matrix.

Neutrophils use chemokine gradients to navigate towards the source of infection, and undergo cytoskeletal rearrangements to migrate through the tissue.

Inflammation is the body's response to harmful stimuli, such as pathogens or damaged cells (The pillars of inflammation).

Two types of Pattern Recognition Receptors (PRR) are involved in the detection of harmful stimuli: Toll-like receptors (TLR) and NOD-like receptors (NLR).

NLRs are intracellular receptors that detect degraded products from phagocytosed pathogens. They include NOD1 and NOD2.

NOD1 recognizes the degraded peptidoglycan of Gram-negative bacteria, while NOD2 recognizes the degraded peptidoglycan of many bacteria.

NOD receptors have a CARD (caspase-recruitment domain) at their terminal end, which allows binding to the CARD on the ends of RIPK2 (receptor interacting serine/threonine kinase 2).

When NOD binds to its ligand, it dimerizes and RIPK2 binds, leading to the phosphorylation and activation of TAK1 (transforming growth factor beta-activated kinase 1).

Activated TAK1 then phosphorylates and activates IKK (Iκβ kinase). IKK degrades Iκβ, which is bound to NF-κB (nuclear factor-kappa B).

NF-κB translocates to the nucleus and induces cytokine production, phagocytosis and defensin synthesis.

RIG-I-like receptors (RLR) are cytoplasmic detection proteins for viral RNA.

RLRs consist of RIG-I and MDA-5, which bind to viral RNA and through CARDs interact with MAVS (mitochondrial antiviral signaling proteins).

Resulting in the phosphorylation of IRF3 (interferon response factor 3), which dimerizes and becomes a transcription factor for type I interferons (IFNs).

Type I IFN signaling induces the interferon response, which prevents viral protein synthesis and production of new virions.

Early responder cells such as neutrophils infiltrate the site of inflammation through selectin and integrin interactions.

Selectins on the surface of vascular endothelial cells are induced by IL-1 and TNF-α, allowing immune cells to roll along the vascular surface.

Integrins on the surface of neutrophils interact with vascular endothelia to firmly adhere the neutrophils to the blood vessel surface.

Neutrophils produce CXCL8 (IL-8) in response to the presence of pathogens, which attracts more neutrophils to the site of inflammation.

Chemokines increase integrin binding and selectin interactions, allowing neutrophils to move through the endothelial cell layer and penetrate the extracellular matrix (diapedesis).

Macrophages also play a role in inflammation by producing chemokines that attract neutrophils to the site of infection.

TNF-α weakens tight junctions and neutrophil proteases loosen PECAM-1 interactions, allowing neutrophils to slide through the endothelial cell layer and penetrate the extracellular matrix.

Neutrophils use chemokine gradients to navigate towards the source of infection, and undergo cytoskeletal rearrangements to migrate through the tissue.