Low-grade inflammation and the brain

What is inflammation?

We usually talk about “inflammation” in relation to infections and injuries. When the body is infected, the immune cells recognize the ‘non-self’ molecules and produce inflammatory factors, called “cytokines”, to coordinate the fight against the infection. Cytokines signal other immune cells and bring them to the site of infection. Inflammation is clinically assessed by measuring cytokine concentrations or other inflammatory markers in the blood and is used as a sign of infection.

What is low-grade inflammation?

It is a question that remains hard to answer. Low-grade inflammation is usually defined as “the chronic production, but a low-grade state, of inflammatory factors”. Conditions characterized by low-grade inflammation are for instance obesity (1), depression (2) or chronic pain (3). Low-grade inflammation does not come from an infection but several physiological mechanisms are involved. Concentrations of inflammatory factors in these conditions are overall slightly higher than in healthy populations, but still remain in the healthy ranges. It is therefore hard to determine whether a specific patient exhibits “low-grade inflammation” but it can be better defined at the level of a group of patients.

Inflammation and the brain

When we are sick, we often want to sleep, have reduced appetite, prefer to stay home alone, have difficulty concentrating and can be a bit moody. All these feelings and behaviors are induced by cytokines! Indeed, in addition to coordinating the fight against infection in the periphery of the body, cytokines also act in the brain and induce behavioral changes (4). All these behavioral changes are adaptive, with the purpose of limiting the spread of the infection and allowing the body to spare energy in order to fight the infection instead of, say, going out partying with friends.

However, the behavioral effects of cytokines are not always beneficial. When the cytokine signal is too strong or lasts a long time, such as in cancer patients during treatment with cytokines, these effects can become maladaptive and lead to more chronic and pathological behavioral alterations, such as depression (5). Inflammation is therefore one hypothesized contributor to depression (4). One critical difference between infection or cancer therapy and most cases of depression is, however, the level of production of inflammatory factors. Cytokine levels are high during immunotherapy, i.e., “inflammation”, while depression is characterized by a state of “low-grade inflammation”.

The proportion of subjects who suffer from depression is higher in conditions characterized by low-grade inflammation than in the general population. For instance, 20 to 30% of obese individuals suffer from depression while the prevalence in the general population is of 5-10% (6). While psychological factors are highly likely  to be involved, we and others investigate the possibility that low-grade inflammation contributes to this psychiatric vulnerability (7). We have notably shown that low-grade inflammation is associated with behavioral changes in obese individuals, such as fatigue (8) or altered cognitive functions (9). One interpretation of this relationship is that the production of inflammatory factors at a low-grade state may be sufficient to induce behavioral alterations and therefore could be one factor participating to the vulnerability to depression.

Low-grade inflammation and chronic pain

The association between low-grade inflammation and behavioral alterations has caused the team of the Behavioral Medicine Pain Treatment Service at the Karolinska University Hospital in Stockholm (Sweden) to wonder whether low-grade inflammation could modulate the efficacy of behavioral treatments for chronic pain. Cognitive and behavioral strategies are indeed the targets of behavioral treatments for chronic pain and low-grade inflammation could prevent the effects of such treatments.

In collaboration with this group, we showed that treatment outcomes were improved in patients with chronic pain and low levels of inflammatory factors while patients with “low-grade inflammation”, i.e., with higher levels of inflammatory markers but still in the healthy range, exhibited less improvement (10).

Although this study was only exploratory, the findings suggest that low-grade inflammation may promote a state of resistance to behavioral treatment for chronic pain and give a potential explanation regarding non-responder patients.

About Julie Lasselin

julie-lasselinDr Julie Lasselin is a “psychoneuroimmunologist”, conducting research assessing the relationships between the brain and the immune system. She got her Ph.D. in 2012 in NutriNeuro in Bordeaux, France. She then has been working as a post-doc at the Department of Clinical Neuroscience (Psychology Division), Karolinska Institute and at the Stress Research Institute, Stockholm University in Stockholm, Sweden. Julie is currently a post-doc in the Institute of Medical Psychology and Behavioral Immunobiology in Essen, Germany and is affiliated to the Karolinska Institute and Stockholm University. Her research focuses on the contribution of inflammation on the development of neuropsychiatric symptoms in vulnerable populations, such as patients suffering from obesity and type 2 diabetes. She carries out both clinical observational studies and experimental studies using the model of administration of lipopolysaccharide (a component of bacterial shell) in humans. She also assesses more specifically the role of inflammation in fatigue and motivational changes, two symptoms that are highly sensitive to inflammation and may explain the psychiatric vulnerability of obese patients.

References

  1. Wellen, K.E. and G.S. Hotamisligil, Obesity-induced inflammatory changes in adipose tissue. J Clin Invest, 2003. 112:1785-8.
  2. Dantzer, R., Depression and inflammation: an intricate relationship. Biol Psychiatry, 2012. 71: p. 4-5.
  3. Parkitny, L., et al., Inflammation in complex regional pain syndrome: a systematic review and meta-analysis. Neurology, 2013. 80:106-17.
  4. Dantzer, R., et al., From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci, 2008. 9:46-56.
  5. Capuron, L. and A.H. Miller, Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther, 2011. 130:226-38.
  6. Evans, D.L., et al., Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry, 2005. 58:175-89.
  7. Capuron, L., J. Lasselin, and N. Castanon, Role of Adiposity-Driven Inflammation in Depressive Morbidity. Neuropsychopharmacology, 2016 (in press).
  8. Lasselin, J., et al., Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun, 2012. 26:1211-9.
  9. Lasselin, J., et al., Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects. Brain Behav Immun, 2016. 58:63-68.
  10. Lasselin, J., et al., Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults. J Behav Med, 2016. 39:916-24.

  Commissioning Editors:  Carolyn Berryman and Neil O’Connell