Leukocyte Recruitment to Infection Sites

• The recruitment of acidic cells to the site of infection is a key function of innate immunity.
• Macrophage cytokines activate cell adhesion molecules, driving endothelium activation.
• Endothelial cells act as a barrier between infection sites and leukocytes.
• Tissue macrophages release cytokines to alert other immune cells to breaches.
• TNF alpha induces the rapid externalization of P selectin-containing granules.
• P selectin is expressed on endothelial cells within minutes.
• mRNA encoding P selectin is synthesized and expressed by endothelial cells when exposed to TNF alpha and IL-8.
• PECAM-1 expression increases and facilitates binding to integrins on circulating monocytes.
• Several adhesion molecule families play an important role in leukocyte recruitment.
• Endothelial cells sense invading microbes and respond to chemical signals.
• These signals stimulate the adhesion of circulating monocytes and neutrophils via adhesion molecules.
• Endothelial cells facilitate the bridge for adaptive immune response activation.
• Leukocyte adhesion deficiency (LAD) stems from a defect in the b2 chain common to LFA-1 and Mac-1.
• People with LAD suffer from recurrent bacterial infections and delayed wound healing.
• Cytokines cause changes in adhesion molecules on endothelial cells and leukocytes.

Key Adhesion Molecules for Leukocyte Recruitment

• Selectins: Membrane glycoproteins that bind specific carbohydrate groups.
  • Expressed on activated endothelium, initiating endothelium-leukocyte interactions.
• ICAMs (Intracellular Adhesion Molecules): Single-pass membrane proteins for tighter adhesion of leukocytes to endothelium.
• Leukocyte Integrins: Two transmembrane protein chains (alpha and beta).
  • Alpha L beta 2 and alpha M beta 2 bind to ICAM-1 and ICAM-2.
  • Integrins allow distinguishing of different cell types (dendritic cells, macrophages, monocytes).
• Extravasation is the migration of leukocytes out of blood vessels.

Steps of Extravasation

• Rolling Adhesion: Weak adhesion between leukocytes and endothelium involves selectins.
  • P selectin appears on the endothelial cell surface within minutes of histamine or TNF alpha exposure.
  • TNF alpha and LPS induce E selectin synthesis, appearing on the endothelial cell surface a few hours later.
  • Selectins recognize the sulfate and sialyl-Lewis X moiety of certain leukocyte glycoproteins.
• Tight Binding: Interactions between leukocyte integrins and adhesion molecules (ICAM-1, ICAM-2).
  • Chemokines bound to proteoglycans signal integrins, increasing leukocyte adhesive abilities.
• Diapedesis: Leukocyte crosses the endothelial wall.
  • Involves leukocyte integrins and PECAM-1 (CD31) expressed on leukocytes and endothelial cells.
• Movement through the basement membrane (diapreneces) with enzymes breaking down extracellular matrix.

Inflammation

• The inflammatory process is critical for controlling infections and is the crowning jewel of the initial innate immune response.
• Inflammation is traditionally defined by the signs: calor (heat), dolor (pain), rubor (redness), and tumor (swelling).
• Microbes penetrating epithelial surfaces trigger an innate immune response.
• Activated macrophages secrete cytokines and complement is activated.
• Cytokines are released and complement is activated.
• Dilation and permeability of blood vessels lead to endothelial cell activation.
• Leukocytes stick to endothelial cells and migrate to the infection site.
• Differentiated phagocytic cells migrate to the infection site by chemotaxis, where phagocytosis occurs.

Process of Inflammation

• Recognition of Harmful Stimuli and phagocytosis: Injury and breach of the skin, microbes enter into the body or damaged cells release DAMPs
• Pattern Recognition Receptors (PRRs): Recognize pathogen-associated molecular patterns (PAMPs) on microbes or damage-associated molecular patterns (DAMPs) released from injured cells.
  • PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and others.
• Phagocytosis: Phagocytic Receptors (e.g., Fc receptors, complement receptors): Recognize and bind to pathogens or opsonized particles.
  • Facilitate the engulfment of microbes or debris by phagocytes.
• Release of Inflammatory Mediators: Cytokines (e.g., IL-1, TNF-α): Induce inflammation, activate immune cells, and regulate the immune response.
  • Released by activated immune cells and stimulate the production of other inflammatory mediators.
  • TNF-alpha causes the upregulation of P-selectin from endothelial cells, causing rolling.
  • TNF-alpha and IL-1 cause the endothelial cells to release IL-8, which upregulates the Expression of sialyl lewis molecules and integrins.
  • Chemokines released from macrophages act as navigators for leukocytes emerging from the blood.
• Tissue damage causes and soluble antibodies binding to bacteria activate the complement system.
  • The complement fragments C3a and C5a bind to mast cells, causing vasodilation and Increased Permeability.
  • Release of histamine: Induce vasodilation and increase vascular permeability. □ Released from mast cells and basophils in response to injury or allergens.
  • Chemoattractants/chemokines/anaphylatoxins from complement leads act as navigators for leukocytes emerging from the blood
• Extravasation: Migration, Rolling , Arrest and adhesion, Diapadesis: PECAM-1 (CD31): Facilitate the migration of leukocytes through endothelial cell junctions. Expressed on endothelial cells and leukocytes.
• Resolution Inflammation: Anti-inflammatory Mediators (e.g., IL-10 lipoxins): Suppress inflammation and promote resolution.
  • Inhibit the production of pro-inflammatory mediators.
• Tissue Repair and Healing: Growth Factors: (e.g. TGF-β, PDGF): Stimulate tissue repair and regeneration. Promote cell proliferation, migration, and extracellular matrix synthesis.
• Dysregulation of inflammation can contribute to chronic inflammatory diseases, autoimmune disorders, and impaired healing.
• Therapeutic interventions targeting inflammatory pathways are used in the treatment of various conditions.
• The duration and intensity of the local inflammatory response must be regulated to control tissue damage and facilitate tissue repair.
• Local inflammation can be accompanied by a systemic response known as acute phase response.
• If the insult is not resolved quickly, systemic acute phase inflammation is initiated.
• Systemic inflammation involves induction of fever, increased synthesis of hormones, and an increase in leukocytosis.
• Leukocytosis is increased, cytokines facilitate a fever that inhibits pathogen growth, and acute phase proteins such as C reactive protein binds to the surface of microbes and activates complement.