Role of IL-1 and TNF in the brain: Twenty years of progress on a Dr. Jekyll/Mr. Hyde duality of the innate immune system

doi:10.1016/j.bbi.2006.12.004

Brain, Behavior, and Immunity

Volume 21, Issue 3, March 2007, Pages 281-289

https://doi.org/10.1016/j.bbi.2006.12.004 Get rights and content

Abstract

The immune-privileged status of the central nervous system (CNS) has changed quite dramatically during the past two decades. Leukocytes have the ability to infiltrate the CNS and cytokines are produced by resident cells, especially during injuries and diseases. Although the cellular source and role of these immune ligands are better known, their exact contribution to brain protection, repair or diseases still remains highly debated today. The ultimate fate of the immune reaction depends on the cytokines involved and the experimental models. It is now generally accepted that microglia play a central role in this response, at least for the production of cytokines participating in the innate immune system. As macrophages, resident microglia produce numerous cytokines and two of them have been largely studied since the beginning of this field of research. Twenty years ago, interleukin 1 (IL-1) and tumor-necrosis factor (TNF) were cloned and recombinant forms were used to investigate their functions ranging from normal neurophysiological responses to pathological conditions. This review presents the history of these two cytokines during immune responses in the brain and where we are now two decades later.

Introduction

Unlike the peripheral organs, the central nervous system (CNS) exhibits a relative absence of lymphatic drainage of the parenchyma, has a limited number of antigen-presenting cells (APCs) and the blood brain barrier (BBB) meticulously filtrates circulating elements. Furthermore, efficiency of every CNS functions and the health of its relatively fragile mostly non-renewable neuronal populations are dependent on tightly regulated extra- and intracellular events, such as the maintenance of strict ionic and glucose equilibrium, efficient removal of excessive metabolites and neurotransmitters, preservation of myelination and axonal integrity (retrograde transport) and proper blood perfusion and oxygenation. The reliance of the CNS on such a delicate state of homeostasis makes it very susceptible to permanent damage and neuronal death when equilibrium is lost in the advent of injuries. The CNS has its own innate immune system, which responds to exogenous pathogenic ligands as well as endogenous proteins produced by stressed or damaged neural cells. The role of this system and its inflammatory components has been intensively studied during the past two decades.

On one hand activation of the innate immune system and cytokine production control infections, remove debris and promote repair but on the other, they may promote various CNS pathologies, ranging from acute injuries to chronic neurodegenerative diseases. Although inflammation is a natural response to pathogens or tissue injuries, there is an on-going debate regarding the extent to which cytokines are involved in CNS homeostasis or diseases. This review highlights and discusses some of the major advancements made in this field since the cloning of the major proinflammatory cytokines, namely IL-1 and TNF-α.

Section snippets

1987: Era of the descriptive ligands

Already by 1987, many studies had concluded that inflammation arises in response to CNS injury (Giulian, 1987). Among the strongest piece of evidence supporting this conclusion was the observation that inflammatory cells, including ameboid microglia and invading blood-derived macrophages, appear in the area of injured neural tissues (Giulian, 1987). Soon thereafter, the hypothesis that inhibiting inflammation may limit clinical deterioration following CNS lesions gained in support, although the

1997: Era of the mechanistic receptors

Extraordinary progress has been made since 1997 in our understanding of the different cellular and molecular mechanisms associated with inflammation and the activity of proinflammatory cytokines and their consequences on the CNS cellular environment under different pathological circumstances. The increasing availability of gene knockout mice, advancements in imaging and histological technologies, along with facilitation in accessing information through the development of computer technologies

2007: Taming the beast

Inflammation is an extremely elaborated sequence of events involving multiple components whose activity seems to be determined by the activity of earlier components. Simply stated, if the beginning programs the end, then modulating the activity of early components may re-reprogram and disorganize the repair process. Importantly, evidence on which this hypothesis is based upon suggest that although impairing the activity of proinflammatory cytokines might translate into a beneficial

Acknowledgment

The Canadian Institutes of Health Research (CIHR) support our research on various projects related to the immune system and the CNS. Serge Rivest holds a Canadian Research Chair in Neuroimmunology. We thank all the students, postdocs and research professionals involved in this research program.

References (52)

D. Giulian et al.
Immunoregulation of cells within the central nervous system
Brain Behav. Immun.
(1988)
G.A. Higgins et al.
Induction of interleukin-1β mRNA in adult rat brain
Mol. Brain Res.
(1991)
K. Jian Liu et al.
Matrix metalloproteinases and free radicals in cerebral ischemia
Free Radic. Biol. Med.
(2005)
P. Parnet et al.
Expression and regulation of interleukin-1 receptors in the brain. Role in cytokines-induced sickness behavior
J. Neuroimmunol.
(2002)
N.J. Rothwell
Functions and mechanisms of interleukin-1 in the brain
Trends Pharmacol. Sci.
(1991)
N.J. Rothwell et al.
Interleukin 1 in the brain: biology, pathology and therapeutic target
Trends Neurosci.
(2000)
Y. Yamasaki et al.
Possible involvement of interleukin-1 in ischemic brain edema formation
Neurosci. Lett.
(1992)
H.A. Arnett et al.
TNFalpha promotes proliferation of oligodendrocyte progenitors and remyelination
Nat. Neurosci.
(2001)
D. Baker et al.
Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins
Eur. J. Immunol.
(1994)
A. Basu et al.
Interleukin-1: a master regulator of neuroinflammation
J. Neurosci. Res.
(2004)

D.E. Brenneman et al.

Cytokine regulation of neuronal survival

J. Neurochem.

(1992)

A.J. Bruce et al.

Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

Nat. Med.

(1996)

E.A. Carswell et al.

An endotoxin-induced serum factor that causes necrosis of tumors

Proc. Natl. Acad. Sci. USA

(1975)

S.T. DeKosky et al.

Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain

Ann. Neurol.

(1996)

M. Delhase et al.

Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation

Science

(1999)

G. Feuerstein et al.

Cytokines in brain ischemia—the role of TNF alpha

Cell. Mol. Neurobiol.

(1998)

V. Fontaine et al.

Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2

J. Neurosci.

(2002)

A. Fontana et al.

Synthesis of interleukin-1/endogenous pyrogen in the brain of endotoxin-treated mice: a step in fever induction?

J. Immunol.

(1984)

K. Frei et al.

Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells

Eur. J. Immunol.

(1987)

D. Giulian

Ameboid microglia as effectors of inflammation in the central nervous system

J. Neurosci. Res.

(1987)

D. Giulian et al.

Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord

Ann. Neurol.

(1990)

D. Giulian et al.

The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain

J. Neurosci.

(1989)

I. Glezer et al.

Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries

FASEB J.

(2006)

E. Hirsch et al.

Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice

Proc. Natl. Acad. Sci. USA

(1996)

N. Hosomi et al.

Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia

J. Cereb. Blood Flow Metab.

(2005)

R.E. Iosif et al.

Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis

J. Neurosci.

(2006)

Cited by (118)

In vivo mechanisms of cortical network dysfunction induced by systemic inflammation
2021, Brain, Behavior, and Immunity
Peripheral inflammation is known to impact brain function, resulting in lethargy, loss of appetite and impaired cognitive abilities. However, the channels for information transfer from the periphery to the brain, the corresponding signaling molecules and the inflammation-induced interaction between microglia and neurons remain obscure. Here, we used longitudinal in vivo two-photon Ca²⁺ imaging to monitor neuronal activity in the mouse cortex throughout the early (initiation) and late (resolution) phases of peripheral inflammation. Single peripheral lipopolysaccharide injection induced a substantial but transient increase in ongoing neuronal activity, restricted to the initiation phase, whereas the impairment of visual processing was selectively observed during the resolution phase of systemic inflammation. In the frontal/motor cortex, the initiation phase-specific cortical hyperactivity was seen in the deep (layer 5) and superficial (layer 2/3) pyramidal neurons but not in the axons coming from the somatosensory cortex, and was accompanied by reduced activity of layer 2/3 cortical interneurons. Moreover, the hyperactivity was preserved after depletion of microglia and in NLRP3^−/− mice but absent in TNF-α^−/− mice. Together, these data identify microglia-independent and TNF-α-mediated reduction of cortical inhibition as a likely cause of the initiation phase-specific cortical hyperactivity and reveal the resolution phase-specific impairment of sensory processing, presumably caused by activated microglia.
Environmental toxins and Alzheimer's disease progression
2020, Neurochemistry International
Alzheimer's disease (AD) is the most common form of dementia, which causes progressive memory loss and cognitive decline. Effective strategies to treat or prevent remains one of the most challenging undertakings in the medical field. AD is a complex and multifactorial disease that involves several risk factors. Aging and genetic factors both play important roles in the onset of the AD, however; certain environmental factors have been reported to increase the risk of AD. Chronic exposure to toxins has been seen as an environmental factor that may increase the risk of developing a neurodegenerative disease such as AD. Exposure to metals and biotoxins produced by bacteria, molds, and viruses may contribute to the cognitive decline and pathophysiology associated with AD. Toxins may contribute to the pathology of the disease through various mechanisms such as deposition of amyloid-beta (Aβ) plaques and tangles in the brain, induction of apoptosis, inflammation, or oxidative damage. Here, we will review how toxins affect brain physiology with a focus on mechanisms by which toxins may contribute to the development and progression of AD. A better understanding of these mechanisms may help contribute towards the development of an effective strategy to slow the progression of AD.
Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib, prevents acute lung injury associated cognitive deficits potentially through suppression of inflammatory response
2020, European Journal of Pharmacology
Acute lung injury (ALI) has been reported to be associated with high mortality rate. Moreover, ALI survivors, frequently present chronic cognitive deterioration. We have previously shown that ‘two hit’ (hydrochloric acid + lipopolysaccharide) induced ALI resulted in cognitive dysfunction through the induction of systemic inflammation. The present study was designed to explore the potential anti-inflammatory effects of olaparib (Poly ADP-ribose polymerase-1 inhibitor), on ALI mediated cognitive impairment. Olaparib was administered at dose of 5 mg/kg body weight (i.p.) 30 min before each hit. Data show that olaparib pre-treatment markedly reduced the neutrophil infiltration, alveolar capillary damage, inflammatory cytokines level (TNF-α/IL-1β/IL-6) and oxidative stress in the lungs at 24 h after ALI induction. Also, olaparib pre-treatment ameliorated the ALI associated cognitive impairment as assessed by Morris water maze test on weekly basis for 2 consecutive weeks. Further, restoration of cognitive function was associated with normalization of serum levels of TNF-α/IL-1β and improved the blood brain barrier (BBB) function, as reflected by data on expression of occludin/claudin-5 and extravasation of Evans-blue/FITC dextran in hippocampus at 1 week post injury. Finally, increased mRNA expression of VCAM-1, TNF-α and IL-1β and NF-κB activation in hippocampus indicate induction of neuro-inflammation, which was downregulated upon olaparib administration. Further, olaparib treatment 1 week after ALI induction blunted the systemic inflammation which was associated with improved BBB and cognitive function. Altogether, our results showed that olaparib protects against ALI and associated cognitive deficits in mice, and thus may offer a new treatment avenue in the area.
Microglial NLRP3 inflammasome activation in multiple sclerosis
2020, Advances in Protein Chemistry and Structural Biology
Multiple sclerosis (MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system (CNS) mediated by autoreactive T cells directed against myelin antigens. Although the crucial role of adaptive immunity is well established in MS, the contribution of innate immunity has only recently been appreciated. Microglia are the main innate immune cells of the CNS. Similar to other myeloid cells, microglia recognize both exogenous and host-derived endogenous danger signals through pattern recognition receptors (PRRs) localized on their cell surface such as Toll Like receptor 4, or in the cytosol such as NLRP3. The second one is the sensor protein of the multi-molecular NLRP3 inflammasome complex in activated microglia that promotes the maturation and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. Overactivation of microglia and aberrant activation of the NLRP3 inflammasome have been implicated in the pathogenesis of MS. Indeed, experimental data, together with post-mortem and clinical studies have revealed an increased expression of NLRP3 inflammasome complex elements in microglia and other immune cells. In this review, we focus on microglial NLRP3 inflammasome activation in MS. First, we overview the basic knowledge about MS, microglia and the NLRP3 inflammasome. Then, we summarize studies about microglial NLRP3 inflammasome activation in MS and its animal models. We also highlight experimental therapeutic approaches that target different steps of NLRP inflammasome activation. Finally, we discuss future research avenues and new methods in this rapidly evolving area.
Immune Mediators of Pathology in Neurobrucellosis: From Blood to Central Nervous System
2019, Neuroscience
Neurobrucellosis, which is the most morbid form of brucellosis disease, presents with inflammatory signs and symptoms. Recent experimental evidence clearly indicates that deregulation of astrocytes and microglia caused by Brucella infection creates a microenvironment in the central nervous system (CNS) in which secretion of pro-inflammatory mediators lead to destabilization of the glial structure, the damage of the blood brain barrier (BBB) and neuronal demise. This review of Brucella interactions with cells of the CNS and the BBB is intended to present recent immunological findings that can explain, at least in part, the basis for the inflammatory pathogenesis of the nervous system that takes place upon Brucella infection.
Two hit induced acute lung injury impairs cognitive function in mice: A potential model to study cross talk between lung and brain
2018, Brain, Behavior, and Immunity
Acute lung injury (ALI), a pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. Interestingly, ALI survivors have been reported for some neurocognitive deterioration at/after discharge. However, the molecular factors behind such extra pulmonary manifestation are not clearly known. The present work was designed to investigate lung-brain cross talk in experimental mice for deciphering primary molecular factors that may be involved in ALI-mediated cognitive impairment. ALI was induced in Balb/c mice by intra-tracheal administration of either 0.1 N HCl (2 ml/kg) or LPS (1 mg/kg) as single hits or both agents were administered successively to mimic the ‘two hit’ model. Interestingly two hit-mediated ALI resulted in exaggerated inflammatory response as reflected by increased pulmonary neutrophils and inflammatory factors (TNF-α/IL-1β/IL-6). Additionally, two hits resulted in delayed resolution of lung inflammation and was coupled with persistent decline in memory, as assessed by Morris water maze test. Further, two hits elevate serum levels of TNF-α/IL-1β which was associated with compromised blood brain barrier (BBB), as evident by decreased expression of occludin/claudin-5 and consequent Evans-blue extravasation in hippocampus 1 week post injury. Finally, dexamethasone protects against the two hit mediated cognitive impairment by lowering the pro-inflammatory factors (TNF-α/IL-1β) both in lungs and blood. Overall, we report for the first time that ‘two hit’ mediated ALI cause persistent cognitive impairment in mice partly via up-regulating systemic expression of TNF-α/IL-1β that may disrupt BBB and hence the model may be a useful tool to examine the lung-brain cross-talk at the molecular level for exploring newer therapeutics.

View all citing articles on Scopus

View full text

Named Series: Twenty Years of Brain, Behavior, and ImmunityRole of IL-1 and TNF in the brain: Twenty years of progress on a Dr. Jekyll/Mr. Hyde duality of the innate immune system

Abstract

Introduction

Section snippets

1987: Era of the descriptive ligands

1997: Era of the mechanistic receptors

2007: Taming the beast

Acknowledgment

Brain Behav. Immun.

Mol. Brain Res.

Free Radic. Biol. Med.

J. Neuroimmunol.

Trends Pharmacol. Sci.

Trends Neurosci.

Neurosci. Lett.

TNFalpha promotes proliferation of oligodendrocyte progenitors and remyelination

Nat. Neurosci.

Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins

Eur. J. Immunol.

Interleukin-1: a master regulator of neuroinflammation

J. Neurosci. Res.

Cytokine regulation of neuronal survival

J. Neurochem.

Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

Nat. Med.

An endotoxin-induced serum factor that causes necrosis of tumors

Proc. Natl. Acad. Sci. USA

Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain

Ann. Neurol.

Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation

Science

Cytokines in brain ischemia—the role of TNF alpha

Cell. Mol. Neurobiol.

Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2

J. Neurosci.

Synthesis of interleukin-1/endogenous pyrogen in the brain of endotoxin-treated mice: a step in fever induction?

J. Immunol.

Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells

Eur. J. Immunol.

Ameboid microglia as effectors of inflammation in the central nervous system

J. Neurosci. Res.

Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord

Ann. Neurol.

The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain

J. Neurosci.

Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries

FASEB J.

Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice

Proc. Natl. Acad. Sci. USA

Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia

J. Cereb. Blood Flow Metab.

Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis

J. Neurosci.

Named Series: Twenty Years of Brain, Behavior, and Immunity
Role of IL-1 and TNF in the brain: Twenty years of progress on a Dr. Jekyll/Mr. Hyde duality of the innate immune system