Neuroimmune Interactions Flashcards
What is a neuroimmune interaction?
A neuroimmune interaction is a integrin between the immune system and CNS. It is a reciprocal and bi-directional flow of information between the brain/CNS and the immune system.
What are the functions of neuroimmune interactions?
• Controls many bodily functions
• Maintain homeostasis and health:
− Intestinal physiology
− Secretory immune function
− Conception and transfer of immunity to offspring
− Sleep
− Recovery from illness → providing host defence against infection, injury, cancer and psychiatric disorders
How is a host defense response to an infection defined?
- Defined as “a coordinated response of an organism to infection in order to eliminate the infection to aid recovery and restore homeostasis”
- Characterised by endocrine, autonomic and behavioural changes
- Some of the responses you will be aware of, others you wont.
- Early recognition of the pathogen by PRRs on the surface of immune cells is the key event in the initiation of the innate immune response.
What is the APR?
- The first phase of a host defense response to infection
- Prevents ongoing tissue damage due to infection
- Aims to isolate and destroy the pathogens
It does this by temporary suspension of homeostasis:
− Induces physiological and behavioural changes → these are detrimental to the pathogen, but beneficial to the host
− Results in clearance of the pathogen, and restoration of normal physiology
• To be effective, the APR must remain acute – if prolonged, it can be detrimental.
What are the 3 parts of the APR?
- Cytokine and APP production
- Metabolic changes
- Sickness behaviour
Describe the cytokine and APP part of the APR
• Infection stimulates immune cells to secrete cytokines via the action of PAMPs on PRRs, such as IL-1, IL-6 and TNFa
• Key role for IL-6:
− Major effect on the hepatic synthesis of APPs.
➢ C-reactive protein → acts as an opsonin
➢ Serum amyloid A → involved in the recruitment of immune cells by inducing enzymes that degrade the ECM.
➢ These APPs act locally to help destroy infection
− Critical in controlling the extent of acute local and systemic inflammation, particularly in decreasing the level of pro-inflammatory cytokines by exerting a protective effect against potential damage and favouring anti-inflamamtory cytokine activity.
− Also promotes B cell differentiation, Ig production and T cell activation
− Is an effective pyrogen
− Is a circulating mediator of HPA axis activation
− Can be used as a biomarker of infection – higher plasma IL-6 correlates with more severe degree of disease
− In acute inflammation, modulates the APR and the over-activity of inflammation. However, chronic IL-6 has a damaging effect by promoting the recruitment of macrophages to the site of injury.
• Role for IL-1:
− Has a direct effect on the HPA axis, through actions on the hypothalamus, causing increased CRH, ACTH and cortisol
− Clear cut differential response to IL-1B and IL-1a
− IV injection of human recombinant IL-1B increased plasma levels of ACTH in a dose-related manner, but IL-1a did not.
− Also stimulates release of GH, TSH, LH and FSH
− Increases the concentration of the noradrenaline metabolite MHPG
• Role for TNFa:
− Endocrine action of TNFa characterized by fever, hepatic synthesis of APP and ACTH & GH secretion.
• Role for IFNy:
− Stimulating factor of the HPA axis, particularly ACTH secretion
− Inhibits GH and TSH production
− Upregulates GC receptor expression on macrophages, suggesting a control mechanism induced during immune activation.
• Role of the HPA axis:
− Activation of the HPA axis is one of the major neuroendocrine features of the APR.
− IL-1, TNFa and IL-6 production during the APR is controlled by intrinsic anti-inflammatory mechanisms (IL-10, IL-1RA, solTNFRs) and by cortisol release.
− During the APR, while innate mechanisms of defence are strongly increased, the activation of the HPA axis exerts a negative modulatory effect on adaptive immunity (mediated by GCs)
➢ Altered levels of GCs and TNFa associated with transitory thymic apoptosis and adaptive immune suppression → thought to be important in controlling potential autoimmune responses.
− Despite evidence suggesting GCs may stimulate inflammation in some circumstances during the early phase of acute stress, activation of the HPA axis is considered the main physiological feedback loop of inflammation
➢ GCs can inhibit the NFkB pathway, IL-12 and IFNy synthesis while they upregulate IL-10, IL-4 and TGFB
➢ This regulatory loop serves as a major regulatory mechanism to prevent tissue damage by inflammatory over-activation
➢ GCs therefore play a fundamental role in controlling and restraining innate inflammatory responses
➢ Failure in GC production or tissue resistance to GC inhibitory effects may result in uncontrolled inflammation and potential damage.
➢ Thus, dysregulation of the HPA axis can increase susceptibility to infection.
Describe the metabolic changes in the APR.
• Protein catabolism – induced by TNFa
• Lipolysis
• Gluconeogenesis
• Hypoferremia and hypozincemia → during infection, we may become deficient in some micronutrietns. This is detrimental to the pathogen, because they need iron and zingc to grow.
− During the APR, hypozincaemia is due to redistribution of zinc among various tissues, particularly the liver.
• Hormonal changes
− Changes in GH seen in some species → thought to act as a counterbalance to reduce the negative metabolic changes occurring in persistent infection. Conversely, given its effects on the immune system, may be an attempt to improve innate immunity.
− Hypercortisolism, hypogonadism
Describe the sickness behaviours that occur in the APR.
. Sickness behavior → these are the things that occur during infection that we are aware of. • Fever • Nausea • Loss of appetite • Loss of body weight • Reduced locomotion • Disturbed sleep • Depression • Mild cognitive impairments
Why would evolution make us feel so ill in order to get rid of bacteria?
• Has been found that under certain conditions, preventing these changes are detrimental and sometimes fatal (forcefeeding mice during bacterial infection can decrease survival time)
• Considered to be the expression of a state that resets the organisms priorities to promote resistance to pathogens and recovery from infection, by preventing the occurrence of activities that are metabolically expensive.
Describe the 5 ways by which cytokines can mediate sickness behaviour within the brain.
- Passive Diffusion
• BBB does not normally allow diffusion due to tight junctions
• However, certain regions of the brain do not have such a tight BBB → these are the CVOs → they have an incomplete and leaky BBB.
− In the CVO, receptors for cytokines an constitutively expressed
− There is also a structural connection between the CVOs and the HPA via the CRH neurons of the PVN.
• Some pathological conditions may also result in BBB breakdown
• There is some evidence against passive diffuseion, as some structures (the median eminence) may have tanycytes (a form of astrocyte) that provide a barrier. - Resident immune cell production of cytokines and diffusion
• There are macrophage like cells in the CVOs and choroid plexus
− These cells respond to PAMPs via TLRs that are constitutively expressed → gives cytokine release → subsequent diffusion into the brain
• IFNa, IFNy, IL-1, IL-6 and TNFa have been shown to be produced in the CNS mainly by astrocyte and microglia
• TGFB, LIF, MIF, IL-10 and IL-18 can be produced by the hypothalamus and pituitary - Receptor/transporter-mediated
• For some cytokines, you may have transporters at the level of brain entry
• This is an active mechanism
• It can become saturable – so the more cytokine you have doesn’t necessarily mean more transport - Indirect actions via second messengers
• Cytokines (eg, IL-1) bind to receptors on perivascular macrophages or endothelial cells of brain venules on the peripheral lumen side.
• This results in the production of a second messenger, eg) PGE2 which is an important mediator of fever, and NO involved in vasodilation
• These are secreted out of the cell on the brain luminal side. - Afferent nerves (rapid effect)
• Locally produced cytokines activate afferent nerves:
− Vagus nerve during abdominal and visceral infecitons
− Trigeminal nerve during oro-lingal infections
• The end terminals express cytokine receptors
• Stimulation of the vagus nerve induces stimulation of several brain areas that are activated by infection – many located in the hypothalamus.
• Transection of the vagus nerve attenuates CNS mediated behavioural responses
• Very rapid → you can see the change before you see the rise of cytokines in the blood
Describe the LPS signalling pathway
- Gram negative bacteria get into the body and undergo proliferation and lysis.
- The release LPS, which binds to LBP (released from the liver)
- This then binds to TLR4
- TLR4 recognizes ligand using accessory protein MD-2. TLR signaling activated by the ligand-induced dimerization of two TLR ectodomains, which brings their cytoplasmic TIR domains close together. This allows them to interact with the TIR domains of cytoplasmic adaptor molecules, such as:
• MyD88 (myeloid differentiation factor 88) - Adaptors recruit IRAK-1 & IRAK-4, which activate the E3 ubiquitin ligase TRAF-6
• Catalyses attachment of ubiquitin to lysine 63 of TRAF-6
• NEMO is also polyubiquitinated - Ubiquitin usually targets protein for degradation, but can also have a signaling role – here it serves as a scaffold that allows recruitment of TAK1.
- TAK1 activates IKK by phosphorylation of its beta subunit.
- IKK phosphorylates IkB at serines 32 and 36. This leads to polyubiquitination of IkB at lysine 48.
- IkB is subsequently degraded by the proteasome.
- NFkB is free to migrate to the nuclease and initiate transcription of pro-inflammatory genes, eg) IL and TNF cytokines.
Describe how LPS activates the HPA axis.
• Mechanism is not well understood, however:
• The hypothesis that LPS increases plasma ACTH levels by releasing IL-1 was tested:
− Adult mice injected with LPS and antibodies against IL-1R
− LPS caused a marked increase in ACTH, but this was blocked with anti-IL-1R
− This suggests that LPS activated the HPA axis though a mechanism involving the IL-1R
− Exogenous admin. of IL-1 mimics most of the effects of LPS on the pituitary
• Another mechanism implicated histamine receptors
− LPS stimulates release of histamine
− Histamine is a known hypothalamic neurotransmitter and activates the HPA axis
What is the link between obesity and the immune response in humans?
- Obesity is associated with an increased prevalence and severity of infections → increased in morbidity in obese septic patients compared with lean people.
- Increased incidence of wound infection after surgery
- Higher rates of infection and mortality after burns
- Higher incidence of respiratory, periodontal and skin infection
What are the obesity-enhanced sickness behaviours in response to LPS in rodents?
• Can investigate changes in immune response to bacterial infection in genetic models of obesity – ob/ob, db/db and fa/fa rats
• Ob/ob mice are leptin deficient → have low metabolism, and eat much more
− Ob/ob mice have severe reduction in food intake in response to infection when compared with healthy controls
− Ob/ob mice die at lower doses of LPS than the controls
These mice have a genetic leptin deficiency – but this doesn’t occur much in humans. The best model is therefore the diet-induced obese mouse.
• When stimulated with LPS, both the control and DIO mice have reduced food intake, but the obese mice have much more dramatic reduction.
• LPS to control animals reduced body weight a little. but it increases back to baseline 4 days post infection. In the DIO mouse, there is a much more severe reduction, and this doesn’t return to baseline.
• LPS stimulation increases body temperature in both control and DIO mice, but it is much higher in DIO mice
Are increased cytokines mediating the increased sickness behaviour in obese mice?
DIO mice show impaired cytokine release in response to infection:
• Less cytokines in the obese animal after LPS
• You don’t see an increase in IL-1RA → so it isn’t that they are antagonizing IL-1
• It could be that you have less anti-inflammatory activity overall, so less IL-1 – it may be that they are suffering worse sickness behavior because their immune system isn’t working properly, and cant get rid of the infection.
Outline what is understood about leptin and sickness behaviour.
Adipokines and immunity: a role of leptin as a neuroendocrine link?
• Leptin is a neuroendocrine signal that is able to inform the immune system of current energy availability
− Negative regulator of food intake and body weight
− 16kDa protein
− Produced predominantly in adipose tissue
− Released into plasma in proportion to adipose tissue mass (Decreased adipose = decreased leptin).
Obese rodents have dysfunctions in leptin signaling:
• Ob/Ob mice have leptin deficiency
• DIO rodents have increased plasma leptin as they are obese, but they become leptin resistant
Leptin is also involved in regulation of immunity:
• Leptin informs the immune system of current energy availability
• Leptin is produced by inflammatory regulatory cells
• Different inflammatory stimuli (LPS, IL1, TNF) regulate the expression of leptin in adipose and into the circulation
• Leptin increases during infection and inflammation
• Leptin can regulate the release of several cytokines, and in turn IL1, IL6 and TNF can increase leptin
• Studies suggest a role for leptin in the development, activation and cytotoxicity of NK cells and the survival, maturation and cytokine production of DCs.
→ Maybe a lack of leptin (or leptin resistance) is involved in enhanced sickness behavior in obese mice
- However, Inhibition of leptin reduces LPS-induced sickness behavior in normal weight rodents (they did not lose weight like those just administered LPS)
- So, in normal body weight rats, circulating leptin mediates the effects of LPS
• In innate immunity, leptin can modulate the over-production of pro-inflammatory cytokines, thus protecting against LPS.
• However, mainly pro-inflammatory during the adaptive response
• However, if leptin mediates sickness behavior:
1. As ob/ob mice are leptin deficienct → they should be resistant to LPS
− But infection causes enhanced sickness behavior
2. As obese db/db mice lack a functional leptin receptor → they should be resistant to LPS
− But infection causes enhanced sickness behavior
→ Other mediators must therefore be involved
→ We don’t yet know what these are
