Principles of danger signals
The body's danger signaling system is based on the recognition of triggers by specialized cellular sensors—pattern recognition receptors (primarily TLR and NOD), as well as dedicated alarmin receptors.
Normally, these receptors respond to exogenous factors—foreign agents such as pathogenic bacteria. However, endogenous signals are generated during local tissue damage. Their appearance is associated with adverse factors that lead to massive cell destruction. It is important to note that physiological programmed cell death (apoptosis) is not accompanied by the release of these substances. Alarmins are released exclusively during necrosis or marked cellular stress, entering the intercellular space and sounding the alarm to surrounding tissues.
Specialized myeloid cells—primarily macrophages and dendritic cells—are responsible for perceiving both exogenous and endogenous signals. Their activation results in the immediate development of innate immune responses (the formation of inflammation), and at later stages, a significant enhancement of adaptive immune responses.
Main types of alarmins
The group of endogenous danger signals is extremely diverse and includes proteins, nucleic acids, and metabolites. The best-studied classes are:
- Heat shock proteins (HSP)
These are the best-known alarmins. In mammals, several variants are distinguished: HSP20, HSP40, HSP60, HSP70, HSP90. In a healthy cell, they function as chaperones, maintaining the optimal spatial conformation of newly synthesized proteins (following subunit assembly and processing). When exposed to stress factors such as temperature changes, radiation, or infection, the expression of HSP increases sharply, and they begin to be secreted extracellularly. In the intercellular environment, they interact with TLRs (specifically TLR-2 and TLR-4), transmitting a distress signal to immune cells.
- HMGB1 protein (High mobility group box 1)
This is a widespread nuclear protein that is secreted during cellular stress and released during necrosis. Its main targets are immune cells. HMGB1 exhibits pronounced chemotactic activity, actively stimulates macrophages, and significantly accelerates the maturation of dendritic cells.
- Uric acid
Upon damage to cellular structures, it is actively released into the extracellular space, where it crystallizes in the form of monosodium urate. These crystals are a potent trigger: they participate in inflammasome function and strongly stimulate the production of pro-inflammatory cytokines.
- S100 proteins
Known as the calgranulin family, they form an extensive group of alarmins involved in the regulation of inflammatory cascades.
In addition, alarmins include bactericidal proteins (such as defensins and cathelicidins), galectins, annexins, and thymosins. Certain cytokines can also perform the function of endogenous danger signals, for example, membrane-bound and cytoplasmic IL-1α.
Cellular mechanisms of innate immunity
The basis for realizing the protective functions of innate immunity is the inflammatory response. The main reason for its development is the need for a rapid and effective response to local tissue damage, as well as to the invasion of exogenous foreign agents (typically pathogenic bacteria).
The initiation of the inflammatory response strictly depends on local cells located directly in the lesion site. Mast cells and tissue macrophages play the main role here. They are the first to detect alarmins released by damaged tissues and trigger a cascade of reactions that recruits other immune cells to the site and forms a full-fledged protective response of the body.
Briefly: answers to topical questions
Which specific cytokines belong to the alarmin group?
The group of cytokines with alarmin function includes interleukin-1 alpha (IL-1α), represented by cytoplasmic and membrane-bound forms.
Which intracellular adaptor proteins are involved in signal transduction from TLRs upon binding to alarmins?
Several intracellular adaptor proteins are involved in signal transduction from Toll-like receptors (TLRs). Upon ligand binding (including alarmins acting via TLR-2 and TLR-4), the signal is transmitted along intracellular pathways involving the following molecules:
- MyD88 — a key adaptor protein of the main dependent cascade.
- Mal — an adaptor functioning together with MyD88.
- TRIF — the first adaptor protein in the MyD88-independent pathway (characteristic of TLR-3 and TLR-4).
- TRAM — an additional adaptor protein for the MyD88-independent pathway from TLR-4.
These proteins transmit intermediate activation products between the links of the signaling chain, ultimately leading to the synthesis of pro-inflammatory cytokines or interferons.
Alarmins—derived from the word "alarm." When a cell is "breached" (necrosis) or "burning" (stress), a molecular alarm system is triggered, and macrophages flock to the sound.
Class and exam questions
Are alarmins released during physiological apoptosis?
No, the danger signaling system is activated only upon necrotic cell death caused by adverse factors. Apoptosis proceeds without a massive release of alarmins.
What is the normal function of heat shock proteins (HSPs)?
In healthy cells, they act as chaperones. Their task is to maintain the correct conformation of synthesized proteins after their processing and assembly from subunits.
Which receptors do heat shock proteins interact with upon entering the intercellular environment?
Acting as alarmins, secreted heat shock proteins bind to pattern recognition receptors, specifically TLR-2 and TLR-4.
Which cells initiate the inflammatory response when danger signals appear?
Inflammation is initiated by local cells residing in tissues, primarily mast cells and macrophages.
What else to study on this topic
- Mechanisms of inflammasome function upon exposure to uric acid crystals.
- Structure and functions of pattern recognition receptors (TLR, NOD).
- The role of macrophages and dendritic cells in perceiving exogenous and endogenous signals.
- The process of dendritic cell maturation under the influence of HMGB1.
- Mechanisms of enhancing adaptive immune responses following the activation of innate immunity.
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