INFECTION, IL-1β, TNF, AND ALZHEIMER’S DISEASE

S. Cristiani^1* and A.D. Procopio²

¹ Local Health Authority ASL Rome 2, Rome, Italy;
² Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy.

*Correspondence to:
Salvatore Cristiani, MD,
Local Health Authority ASL Rome 2,
Via Giustiniani, 12,
00186 Rome, Italy.
e-mail: cristianisalvatore@gmail.com

ABSTRACT

Interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF) are two molecules that regulate the immune system, but they are also highly inflammatory cytokines. IL-1β and TNF are produced primarily by monocytic cells and macrophages, but can also be generated by non-immune cells such as fibroblasts, endothelial cells, muscle cells, and others. IL-1β and TNF can be activated by pathogenic microorganisms and can induce systemic inflammation and fever, leading to septic shock. IL-1β  and TNF are linked to the nervous system through the neuroimmune axis, a continuous cross-talk between the immune system and the brain. The influence of IL-1β and TNF on the central nervous system (CNS) manifests itself through their action on the hypothalamus, producing fever and neuroinflammation with microglia activation and increased blood-brain barrier (BBB) permeability, effects that can contribute to degenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis, and Parkinson’s disease. In AD, IL-1β and TNF are produced primarily by activated microglia in response to the accumulation of β-amyloid. Increased IL-1β in affected brain areas stimulates microglial activation, while elevated TNF in the brain and cerebrospinal fluid is protective at low concentrations and neurotoxic at high levels and can induce apoptosis. Therapies that block IL-1β and TNF improve the neuroinflammatory process.

KEYWORDS: Alzheimer’s Disease, infection, cytokine, neuroinflammation, immunity

INTRODUCTION

Interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF) are cytokines that regulate the immune system and are produced primarily by macrophages and other immune and non-immune cells such as fibroblasts, endothelial cells, muscle cells, and others (1). IL-1β and TNF are mediators of inflammation and fever and are major activators of endothelial cells. When these cytokines are overproduced, they attract neutrophils to the inflammatory site, increasing local inflammation.

IL-1β and TNF are activated by pathogenic microorganisms and can also induce systemic inflammation, leading to toxic shock syndrome (2). Sepsis and septic shock are primarily mediated by TNF, which induces IL-1β, while acute bacterial infections are mediated by both cytokines (3). Some autoimmune inflammatory diseases, such as rheumatoid arthritis, are mediated primarily by IL-1β and TNF, while in Crohn’s disease, the predominant cytokine is TNF (4,5).  For Crohn’s disease, the anti-TNF drug infliximab is used, while for rheumatoid arthritis, anakinra (anti-IL-1) is used.

Bacteria, viruses, fungi, and parasites can activate cells of the immune system, resulting in the production of pro-inflammatory cytokines such as IL-1β and TNF. Early immune defense cells such as macrophages, neutrophils, and dendritic cells recognize microbes through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) (6). These receptors are recognized by pathogen-associated molecular patterns (PAMPs), which are microbial components, lipopolysaccharide (LPS) from Gram-negative bacteria, peptidoglycan, and viral RNA, among others (7).  PRR activation leads to intracellular NF-κB signaling, inflammasome activation, and the production of inflammatory cytokines (8).  Among the biological effects of IL-1β, it is worth noting its action on the hypothalamus, producing fever, while on the endothelium, it causes increased vascular permeability (9). Furthermore, IL-1β affects neutrophil recruitment and endothelial cell activation (10). TNF is also a potent pro-inflammatory molecule that promotes vasodilation and blood vessel permeability and helps recruit immune cells, including macrophages and neutrophils (11). IL-1β induces TNF, and vice-versa, creating a synergetic effect that augments inflammation. IL-1β and TNF stimulate the production of arachidonic acid, which in turn generates prostaglandins and leukotrienes, powerful mediators of inflammation and pain (12).

DISCUSSION

IL-1β and TNF are pro-inflammatory cytokines involved in important immune processes for the body’s survival but also contribute to many inflammatory diseases (13).  They stimulate each other, and when one is generated and released in response to stimuli, including infections or tissue damage, it can stimulate the other.

IL-1β and TNF have similar redundant effects, as seen in vascular permeability, fever, and macrophage activation (14). The synergistic effect of these two cytokines can worsen the inflammatory state. IL-1β and TNF cause tissue damage primarily through their ability to recruit inflammatory immune cells (15).  These two cytokines stimulate various cellular responses involving a variety of cells, such as macrophages, lymphocytes, neutrophils, and mast cells.

IL-1β and TNF act on blood vessels by increasing permeability and activating vascular endothelial growth factor (VEGF). IL-1β and TNF have different receptors and can therefore act synergistically. Bacteria, viruses, fungi, and parasites enter the human body and stimulate innate immune cells, which generate IL-1β and TNF. Innate immune cells are primarily macrophages and dendritic cells, considered sentinel cells, that recognize PAMPs via PRRs, which include TLRs and NOD-like receptor receptors (16). These reactions lead to the intracellular activation of NF-kB and MAPK signalling pathways, resulting in the production of pro-inflammatory cytokines, including IL-1β and TNF (17). However, IL-1β and TNF exhibit different biological effects (18).

IL-1β recognizes PAMPs and damage-associated molecular patterns (DAMPs) and activates the inflammasome, while TNF recognizes microbes and triggers the activation of T and natural killer (NK) cells (19). Furthermore, IL-1β activates the endothelium, causing the expression of adhesion molecules that promote leukocyte recruitment, increases vascular permeability, and activates macrophages and neutrophils (20). TNF acts similarly to IL-1β on the endothelium and vascular permeability, causes strong immune cell recruitment through chemokines, and induces apoptosis in some cells (21). At the systemic level, IL-1β is the endogenous pyrogen that induces fever by acting on the hypothalamus, where it stimulates prostaglandins and increases acute-phase reactants (9). TNF, on the other hand, is less potent in inducing fever, activates lipid and protein metabolism, and at high concentrations causes septic shock with hypotension and disseminated intravascular coagulation. Both cytokines are key acute-phase reactants, but TNF is more closely associated with systemic damage, while IL-1β is more associated with fever and inflammasomes. However, a strong induction of local inflammation leads to systemic inflammation (22).

Acute molecular inflammation

Acute molecular inflammation induced by microorganisms is an immediate defensive response of the human body against infectious agents. It is a complex process involving immune cells, chemical mediators, and recognition receptors. TLRs, NOD-like receptors, and RIG-1 recognize PAMPs, which are characteristic molecules such as LPS from Gram-negative bacteria, peptidoglycans, and viral RNA (23). They also recognize DAMPs released by damaged cells (24). These events are followed by the activation of immune cells such as macrophages, dendritic cells, mast cells, and neutrophils. Macrophages produce cytokines, mast cells release histamine and other chemical mediators, and neutrophils, attracted by chemokines (such as IL-8), migrate to the infection site by chemotaxis (25). Together, these processes fuel inflammation and produce clinical symptoms. Other molecular mediators are the complement system (which helps lyse microorganisms), prostaglandins and leukotrienes which cause vasodilation, and reactive oxygen species which participate with their enzymes in destroying pathogens.

Chronic inflammation

Chronic inflammation differs from acute inflammation because it persists over time.  Microorganisms often remain at the inflamed site and infection is difficult to eliminate, continuously stimulating the immune system. Some of the microorganisms that induce chronic inflammation is Mycobacterium tuberculosis and Helicobacter pylori. Viruses that induce hepatitis (B or C) not only cause chronic inflammation but can also cause liver cancer (26).  In the continuous immune activation exerted by these microorganisms, the adaptive immune response (T and B lymphocyte response) prevails, in addition to the innate immune response (27). Chronic inflammation causes progressive tissue damage, due not only to the pathogen but also to inflammatory molecules produced by host cells. During the recognition phase, PRR stimulation (TLR, NOD-like, and RIG-I) by PAMPs, such as bacterial peptidoglycan or chronic viral RNA, persists (28).  In addition, there is activation of PAMPs from damaged cells.

CD4⁺ T lymphocytes (Th1 and Th17) produce interferon-gamma (IFN-g) and IL-17, which stimulate macrophages and attract neutrophils to the inflammatory site (29).  In this context, B lymphocytes activated by IL-4 from T cells continuously produce antibodies and can sometimes also produce autoantibodies. Fibroblasts are stimulated by transforming growth factor-beta (TGF-b) and generate collagen, which induces fibrosis (30). Chronically produced cytokines and proteases degrade the extracellular matrix, while TGF-b participates in wound healing and fibrosis (31). These events can lead to the formation of granulomas, chronic fibrosis, and a risk of cancer.

Alzheimer’s Disease

Much modern research is devoted to the study of Alzheimer’s Disease (AD), whose exact cause remains unknown to this day. The difference between a healthy brain and one affected by AD is based on ventricular dilation; the more serious the disease, the more dilation is observed (32). AD is characterized by the formation of tau proteins and β-amyloid (33).  The anomaly of tau protein twists to form plaques and tangles which can damage neurons and cause the death of cells (34). However, there are cases in which AD is caused by accumulation of the protein y-synuclein, which causes vascular damage (35). Tau protein aggregates and damages neurons, while β-amyloid forms plaques that inflame brain tissue and activate and engulf microglia, which subsequently produce inflammatory cytokines (36) (Fig.1).

Fig. 1. Steps leading to cell death and inflammation in Alzheimer’s disease (AD). Tau protein aggregates and causes neuronal damage resulting in the death of neurons. β-amyloid forms plaques which aggregate and induce and engulf microglia, resulting in the activation and release of inflammatory cytokines.

CONCLUSIONS

IL-1β and TNF are cytokines produced primarily by macrophages and other innate immune cells in response to pathogenic microorganisms such as viruses, bacteria, fungi, and parasites, but when produced in excess, they are powerful pro-inflammatory molecules. IL-1β and TNF are generated after activation of innate immune receptors, including TLRs. These two cytokines are released when innate immune receptors recognize microbial components such as PAMPs. Among the most important effects of IL-1β and TNF are fever, increased vascular permeability, and leukocyte recruitment.

Conflict of interest

The authors declare that they have no conflict of interest.

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