General principles of receptor interaction
The action of various ligands (both foreign pathogens and endogenous cytokines) on the receptors of innate immune cells triggers a complex cascade of processes.
First, endocytosis is activated—the mechanism of engulfing and digesting foreign agents. This is followed by activation, which consists in mobilizing intracellular defense reserves and actively secreting factors that regulate the immune response. The specific pathway of the reaction depends on the nature of the primary signal.
Main types of macrophage activation
Depending on the triggering factors, three key pathways of macrophage polarization are distinguished, each characterized by its own set of secretory products, enzymes, and surface markers.
1. Classical activation
Directed toward the aggressive elimination of the threat.
- Activating signal: Interferon-gamma (IFNγ) combined with tumor necrosis factor (TNF) via Toll-like receptors (TLR).
- Enzymatic profile: Sharp increase in NO synthase and a drop in arginase levels.
- Surface markers: Upregulation of MHC-II and CD86, but downregulation of mannose-binding receptors and Fcγ-RII.
- Secretion: Pro-inflammatory cytokines (↑TNF, ↑IL-12, IL-1, IL-6) and chemokines (IP-10, MIP-1α, MCP-1).
- Biological effect: Enhanced bactericidal and tumoricidal activity, active antigen presentation.
2. Alternative activation
Aimed at suppressing inflammation and restoring homeostasis.
- Activating signal: Interleukins IL-4 and IL-13.
- Enzymatic profile: High arginase activity with suppressed NO synthase.
- Surface markers: Increased number of mannose-binding receptors, scavenger receptors, and CD23 (with decreased CD14).
- Secretion: Anti-inflammatory factors (↑IL-1RA, IL-10) and chemokines (PARC-1, MDC, TARC).
- Biological effect: Accelerated regeneration of damaged tissues, suppression of T-cell proliferation, and a marked decrease in bactericidal activity.
3. Type II activation
A specific regulatory pathway.
- Activating signal: Immune complexed immunoglobulin G (IgG) together with TLR, CD40, or CD44.
- Enzymes and markers: Decreased NO synthase. Upregulation of MHC-II and CD86 on the membrane.
- Secretion: High levels of IL-10 with decreased IL-12 (along with TNF, IL-1, IL-6). Secreted chemokines remain currently unknown.
- Biological effect: Pronounced anti-inflammatory activity and stimulation of antibody production.
Biological danger: DAMPs and Alarmins
Modern understanding of defense is based on the concept of endogenous danger signals. The immune system reacts not only to external microbes but also to signs of internal destruction.
- DAMPs (Danger-associated molecular patterns) are molecules perceived by the body as alarm signals. The term was coined by analogy with PAMPs (pathogen-associated molecular patterns).
- Alarmins are a special group of endogenous substances that serve as physical carriers of these signals. They are widely present in normal cells but remain sequestered inside until a catastrophe occurs.
Characteristics of alarmins:
- They are upregulated exclusively during necrotic tissue damage and cellular stress.
- During programmed cell death (apoptosis), alarmins are strictly not released, which is why apoptosis proceeds without inflammation.
- Their primary target is the immune system (most frequently they activate dendritic cells).
- The mechanism of action is mediated through receptors that sometimes overlap with receptors for microbial PAMPs.
Briefly: answers to topical questions
Which specific endogenous molecules are classified as alarmins?
- Heat shock proteins (HSP) are the best-known alarmins; mammalian variants include HSP20, HSP40, HSP60, HSP70, and HSP90.
- HMGB1 protein is a widely distributed chromatin-associated protein released during necrotic cell death.
- Uric acid is released upon cell damage, forming monosodium urate crystals.
- S100 proteins are a family of calgranulins that form a large group of alarmins.
- Other alarmins include bactericidal proteins defensins and cathelicidins, galectins, thymosins, annexins, as well as cytoplasmic and membrane-bound IL-1α.
Which transcription factors regulate classical macrophage activation?
- NF-κB factor is activated upon binding of PAMPs to TLRs on macrophages via the MyD88 adaptor protein, as well as via contact-dependent stimulation through CD40.
- c-Jun factor is triggered as a result of the activation of the Rac-dependent branch of the MAPK cascade during contact-dependent stimulation.
- STAT1 factor is activated by Jak1 and Jak2 kinases via the cytokine mechanism mediated by the binding of IFNγ to its receptor.
Which innate immune cell receptors recognize PAMPs and DAMPs?
- Toll-like receptors (TLRs) recognize PAMPs; for alarmins, HSP interaction with TLR-2 and TLR-4 is noted.
- NOD-like receptors (NLRs) recognize peptidoglycans; NALPs participate in inflammasome formation.
- RIG-like receptors (RLRs) recognize foreign viral RNA.
- Scavenger receptors bind lipoproteins, lipopolysaccharide, lipoteichoic acid, and apoptotic cells.
- Sources also indicate the existence of dedicated alarmin receptors, though a specific complete list of such receptors has not been provided.
What types of tissue macrophages exist in the human body?
- Kupffer cells are hepatic stellate macrophages located between blood vessels and hepatocytes.
- Alveolar macrophages are pulmonary macrophages capable of migrating into the alveolar lumen (pleural and peritoneal macrophages are also distinguished).
- Microglia are resident macrophages of the central nervous system.
- Mesangial cells are renal macrophages.
- Osteoclasts are bone tissue macrophages.
- Other types include connective tissue histiocytes, type A synovial cells in joints, and macrophages of the thymus and secondary lymphoid organs.
Classical kills (NO synthase is active, bacteria perish), Alternative saves (arginase is active, regeneration takes place).
Class and exam questions
What is the main enzymatic difference between the classical and alternative pathways?
During classical activation, NO synthase levels increase while arginase drops, whereas during alternative activation, the opposite occurs—arginase dominates while NO synthase is reduced.
Are alarmins released during natural cell death (apoptosis)?
No. Alarmins are expressed exclusively during necrotic damage and cellular stress, but strictly not during apoptosis.
Which receptors are involved in type II activation?
Type II activation is triggered through the interaction of IgG complexes with TLR, CD40, or CD44 receptors.
What else to study on this topic
- Mechanisms of phagocytosis and endocytosis of foreign agents
- The role and types of Toll-like receptors (TLRs) in the immune response
- PAMPs: pathogen-associated molecular patterns
- Cytokines and chemokines: classification and functions
- Antigen presentation and the role of MHC-II molecules
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