Chemokines and Cell Adhesion

Lecture Overview: Leukocyte Trafficking, Chemokines, and Cell Adhesion

  • Instructor Information:
    Prof. Mei Chen
    Email: m.chen@qub.ac.uk
    Queen's University Belfast

Learning Outcomes

  • By the end of this lecture, students will:

    • Understand the structure and function of chemokines.

    • Comprehend the multiple steps of leukocyte trafficking under inflammatory conditions.

    • Gain knowledge of key adhesion molecules and chemokines involved in each step of leukocyte trafficking.

Lecture Structure

  • The discussion will include:

    • The relationship between leukocyte trafficking and inflammation.

    • The significance of chemokines in immune cell trafficking, including:

    • Definition of chemokines.

    • Classification of chemokines.

    • Functions of chemokines.

    • Mechanisms of leukocyte movement from circulation to inflamed sites.

    • The roles of adhesion molecules and chemokines in this process.

Recap on Inflammation

  • Signs of inflammation include:

    • Redness

    • Swelling

    • Heat/Fever

    • Pain

    • Impaired/loss of function.

  • Inflammation is a host response to damage/injury.

Causes of Inflammation

  • Exogenous Factors:

    • Microbial: Bacteria, viruses, parasites.

    • Non-microbial: Allergens, toxic compounds, burns.

  • Endogenous Factors:

    • Damage-associated molecular patterns (DAMPs).

    • Intermediate metabolic products.

Immune Cell Types Involved in Inflammation

  • Cell Types:

    • Neutrophils

    • Eosinophils

    • Basophils

    • Mast cells

    • Lymphocytes

    • Monocytes

Mechanism of Leukocyte Trafficking

  • Key Points:

    • Declarative understanding of circulation through lymph nodes, the spleen, and the site of inflammation.

    • Physiology of leukocyte trafficking:

    • Distinction between normal and inflamed retinal conditions and leukocyte interactions with endothelial cells.

  • Questions Addressed:

    • How do leukocytes determine their path to fight pathogens?

    • Mechanisms enabling leukocytes to cross blood vessels.

Chemotaxis

  • Definition:

    • Chemotaxis refers to cellular movement in response to chemical signals guiding leukocytes to pathogen sites.

Recap on Cytokines

  • Definition:

    • Cytokines are low molecular weight proteins that bind to receptors, triggering signaling pathways in immune response.

  • Classification:

    • Cytokines can be classified functionally or by their membrane receptors.

    • Different leukocytes express varied chemokine receptors categorized into five families.

Key Cytokines and Their Functions

  • Examples:

    • IL-1β: Local tissue destruction, activating vascular endothelium.

    • TNF-α: Activates lymphocytes, promotes increased vascular permeable leading to IgG and complement access.

    • IL-6, CXCL8, IL-12: Promote lymphocyte activation and recruit neutrophils to infection sites.

Chemokines: Overview

  • Definition:

    • Chemokines are small chemoattractant proteins stimulating the migration and activation of phagocytic cells and lymphocytes, playing a central role in inflammatory responses.

  • Characteristics:

    • Defined by structure and classified/named based on conserved cysteine patterns.

Structure of Chemokines

  • Classification:

    • Chemokines exhibit unequal distribution among four classes based on their structural characteristics.

Chemokine Receptors

  • Architecture:

    • Chemokine receptors possess a seven transmembrane (7TM) structure and couple with G-proteins for signal transduction.

    • Characteristic motifs include the “DRY” motif, crucial for function.

Interactions of Chemokine Receptors

  • Multiple ligands possible, but classifications are restricted.

  • Examples of key ligands:

    • CCL11, CCL3, CCL5, CCL2, etc.

Functional Classification of Chemokines

  • Homeostatic Chemokines:

    • Regulate normal immune cell movement under non-inflammatory conditions.

    • Guide immune cells to lymphoid organs, e.g., CCL19 guides naïve T cells to lymph nodes.

  • Inflammatory Chemokines:

    • Recruit immune cells from the bloodstream to sites of inflammation (e.g., CXCL8, CCL2, CCL3).

Mechanisms of Leukocyte Migration to Pathogens

  • Concept of Chemotaxis:

    • Pathogens produce chemoattractants; tissue cells are stimulated to create these signals, directing immune cells expressing chemokine receptors to the inflammation site.

Steps of Leukocyte Passage Through Blood Vessels

  • Stages:

    1. Tethering and Rolling

    2. Firm Adhesion

    3. Trans-migration

    4. Migration towards the inflammatory site.

Step 1: Tethering and Rolling

  • Normal rolling of leukocytes past endothelial cells is mediated by selectins.

    • Tethering speed: 4000 microns/sec, rolling at 40 microns/sec.

    • Cytokines inducing selectins include C5a, histamine, TNF-α, LPS, etc.

Selectins: Role and Function

  • Definition:

    • Selectins are single-chain transmembrane glycoproteins that bind carbohydrates in a Ca2+-dependent manner.

    • Types of Selectins:

    • Leukocyte: L-Selectin (Cd62L)

    • Endothelial: P-Selectin & E-Selectin

Step 2: Firm Adhesion

  • Crucial molecules: Intercellular adhesion molecules (ICAMs) on endothelial cells; integrins expressed by leukocytes.

    • Activation by chemokines increases their adhesion abilities.

Integrins: Mechanisms

  • Definition:

    • Integrins are two-chain molecules that bind to Ig superfamily molecules and extracellular matrix components inducing high-affinity states upon cell activation.

    • Structure: Comprised of α and β subunits.

Step 3: Trans-Endothelial Migration

  • Mechanism:

    • Matrix metalloproteases digest the basement membrane.

    • Platelet endothelial cell adhesion protein 1 (PECAM-1) facilitates junctional passage of leukocytes.

Step 4: Migration Toward the Inflammatory Site

  • Gradient Formation:

    • Chemokine gradients aid in directing leukocyte migration to sites of inflammation.

Phases of Inflammation

  • Differentiation of leukocyte recruitment based on inflammation stage.

  • Roles of Immune Cells:

    • Distinct roles played by different immune cells during inflammation.

Outcomes of Acute Inflammation

  • Positive Outcomes:

    • Resolution of inflammation: removal of stimuli, cellular clearance, and tissue repair.

  • Negative Outcomes:

    • Chronic inflammation, tissue damage, fibrosis, and abscess formation.

Clinical Implications and Conditions Linked to Inflammation

  • Chemokine inhibitors/antagonists suppress immune cell activation (e.g., CCR5 inhibitors like maraviroc).

  • Integrin-based therapeutics:

    • Applications for thrombotic complications from platelet αIIbβ3 inhibitors.

    • Use in multiple sclerosis and Crohn’s disease with lymphocyte α4β1 and α4β7 inhibitors.

Laboratory Markers of Inflammation

  • Examples: CRP (C-reactive protein), leukocytosis.

Closing Thoughts

  • Key Questions to Reflect On:

    • The relationship between leukocyte trafficking and inflammation.

    • Importance of chemokines in immune cell trafficking.

    • The classification and functionality of chemokines.

    • Detailed steps of leukocyte movement to inflamed sites and the molecules involved.

Recommended Reading Materials

  • Janeway's Immunobiology (9th Ed, 2017, pp. 111-118).

  • Charo IF, Ransohoff RM. The roles of chemokines and receptors in inflammation. N Engl J Med. (2006).

  • Hyun YM, Hong CW. Insights into neutrophil trafficking. J Leukoc Biol. (2017).

  • Salmi M, Jalkanen S. Control of leukocyte trafficking. Nat Rev Immunol. (2005).

  • McEver RP et al. Selectin-carbohydrate interactions in leukocyte trafficking. J Biol Chem. (1995).

  • Other relevant articles covering recent findings and reviews on leukocyte trafficking.