Neuroimmune mechanisms in chronic inflammation : translational studies of the inflammatory reflex

A functional immune system is crucial for our survival from the pathogens and toxins we are constantly subjected to. For reasons only partially understood, in some individuals the immune response instead target self antigens, as suggested in rheumatoid arthritis (RA), or environmental non-pathogenic antigens, as suggested in allergy, leading to a failure of resolution and development of a state of chronic inflammation. Although current treatment strategies are largely effective at treating the peripheral inflammation, symptoms that can be attributed to the central nervous system (CNS) such as pain sensitization or fatigue often persist, causing considerable distress for the patient. A growing amount of evidence point towards that chronic inflammatory diseases are accompanied by central inflammation which could then be involved in driving CNS related symptoms.

In general, the immune response may result in damage not only to the pathogen but also to healthy tissues in the vicinity. Therefore it is essential that an inflammatory process is concluded as soon as the threat is cleared. Recently, the cholinergic anti-inflammatory pathway (CAP) was described promoting a fast vagus mediated control of systemic inflammation. The anti-inflammatory potential of CAP initiated clinical trials exploring the use of vagal stimulation as an alternative treatment strategy for immune suppression in human chronic inflammatory diseases such as rheumatoid arthritis. Even so, much remain to be understood regarding the mechanism of CAP and its anti-inflammatory extent.

In this thesis, work has been undertaken to explore the role of central nervous mechanisms in RA and seasonal allergy. Furthermore, CNS involvement in RA and other arthropaties was studied by mapping the cerebrospinal fluid proteome and its treatment associated changes. Additionally, CAP mechanisms were studied using animal models of endotoxaemia in a translational fashion. Whereas we could not detect an increased brain microglial activity in either RA or Allergy, we further confirm a state of autonomic dysregulation in RA with close associations to peripheral inflammation. We demonstrate for the first time that modern treatment strategies not only exert effects peripherally, but also lead to a central nervous reduction of inflammatory related proteins. We additionally identify several of these proteins as potentially important players to study further in the context of neuro immune responses. Furthermore, we provide evidence that the dependence of prostaglandins for a functional CAP is located to splenic events, demonstrating that prostaglandin E2 is important for acetylcholine production as well as immunosuppressive function in splenocytes. In addition, an activated CAP is shown to exert effects on additional immune cells and immune compartments than previously known.

Taken together, this thesis has contributed to further our understanding of CNS involvement in chronic inflammatory conditions, of effects exerted by commonly used as well as experimental treatment strategies and neural regulation of inflammation. In the future, the results here presented may hopefully benefit the patient by contributing to the development of improved treatment strategies and better understanding of disease pathology.

List of scientific papers

I. Forsberg A, Lampa J, Estelius J, Cervenka S, Farde L, Halldin C, Lekander M, Olgart Höglund C, Kosek E. Cerebral glia activity in patients with rheumatoid arthritis. [Manuscript]

II. Tamm S, Cervenka S, Forsberg A, Estelius J, Grunevald J, Gyllfors P, Karshikoff B, Kosek E, Lampa J, Lensmar C, Strand V, Åkerstedt T, Halldin C, Ingvar M, Olgart Höglund C, Lekander M. Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [C-11]PBR28 PET study. Brain Behavior and Immunity. 2018; 68: 146-157.
https://doi.org/10.1016/j.bbi.2017.10.013

III. Estelius J, Lengqvist J, Ossipova E, Idborg H, Le Maître E, Andersson LA M, Brundin L, Khademi M, Svenungsson E, Jakobsson PJ, Lampa J. Mass spectrometry based analysis of cerebrospinal fluid from arthritis patients – Immune related candidate proteins affected by TNF-blocking treatment. [Manuscript]

IV. Estelius J, Le Maître E, Revathikumar P, Chemin K, Lampa J. Vagus nerve stimulation decreases activation of select CD4+ T cell populations and NK cells in LPS-treated mice. [Manuscript]

V. Revathikumar P, Estelius J, Karmakar U, Le Maître E, Korotkova M, Jakobsson PJ, Lampa J. Microsomal prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of the cholinergic anti-inflammatory pathway in endotoxaemic mouse spleen. Plos One. 2018, 13 (2):20, e0193210.
https://doi.org/10.1371/journal.pone.0193210