Bedeutung des Zusammenspiels von Zytokinen und Monaminen auf diversen ZNS-Niveaus für Verlauf und Suszeptibilität einer Arthritis
Zusammenfassung der Projektergebnisse
Previous studies in our laboratory demonstrated a severe disruption of the brain-immune system-joint communication during the course of CII-induced arthritis in DA rats. The reasons for this phenomenon are still not clarified. Three hypotheses emerged, which we tested during the present grant period: a) CII immunization of non-susceptible PVG rats results in protective changes in central and peripheral neuroendocrine responses that are different from those observed in highly susceptible DA rats; b) Experimental disruption of protective stress axes in non-susceptible PVG rats affects the expression of arthritis; and c) A defect in cholesterol delivery to or uptake by adrenocortical cells, immune cell infiltration into the adrenal gland, and changes in adrenocortical mitochondria contribute to the adrenal inability to produce adequate amounts of steroid hormones during CII arthritis in DA rats. To test the first hypothesis (a), we compared central and peripheral neuroendocrine and immune parameters in highly susceptible DA rats and non-susceptible PVG rats under basal conditions and following CII immunization. The outcome of these studies confirmed this hypothesis as demonstrated by the following results. As compared to DA rats, PVG rats had a stronger basal tone of the HPA axis and the SNS, as reflected by corticosterone and adrenaline blood levels prior to immunization. In parallel, PVG rats had basally a lower pro-inflammatory cytokine load than DA rats, as evaluated by plasma IL-1β and IL-6 levels. Although only a small number of PVG rats developed minimal symptoms of arthritis in contrast to a severe arthritis in all DA rats, anti-collagen type II antibody levels were significantly higher in PVG rats than in DA rats. This shows that non-susceptible PVG animals can produce a good immune response to collagen type II. However, DA rats mounted a stronger peripheral pro-inflammatory cytokine response than PVG rats. Since no overt increase in corticosterone blood levels were observed in immunized PVG rats, a likely possibility is that these animals are protected from developing arthritis by a high basal tone of neuroendocrine factors, particularly by high corticosterone blood levels, which were about 3-fold higher in non-immunized PVG than in nonimmunized DA rats. In support of this possibility are the results that confirm our second hypothesis (b), by showing that disruption of the HPA axis in PVG rats by adrenalectomy markedly exacerbated arthritis in this otherwise resistant strain. These data confirm the importance of an intact brain-immune system-joint communication, here in particular of the HPA axis, for the severity of arthritis and demonstrate that the tone of the HPA axis prior to and after immunization is a critical element for the susceptibility to develop the disease. Finally, it was our third aim (hypothesis c) to elucidate mechanisms responsible for this relative adrenal insufficiency during arthritis. The results obtained confirm our third hypothesis and demonstrate an increased infiltration of immune cells in the adrenals, ultrastructural alterations of adrenocortical mitochondria and a reduced lipid breakdown in adrenocortical cells during arthritis in DA rats. In conclusion, our results demonstrate for the first time that CII immunization of resistant PVG rats results in central and peripheral cytokine and neurotransmitter changes different from those observed in susceptible DA rats. These differences may underlie the distinct susceptibility to a wide range of inflammatory autoimmune diseases, such as arthritis. This possibility was strongly supported by the second important finding of the present application period, which shows that mimicking the disturbed brain - immune system - joint communication observed in arthritic DA rats resulted in the expression of arthritis in otherwise resistant PVG rats. These remarkable findings indicate the relevance and important modulatory function of an efficient brainimmune system-joint communication, here in particular of the HPA axis, for the susceptibility to develop inflammatory autoimmune diseases, as experimental arthritis. Moreover, the data suggest that intra-adrenal DCs and hence an immune-adrenal crosstalk as well as adrenocortical mitochondrial dysfunction and a reduced lipid breakdown in adrenocortical cells probably influence the glucocorticoid production during arthritis in a negative manner and, thus, contribute to the manifestation of arthritis.
Projektbezogene Publikationen (Auswahl)
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Disrupted brain-immune system-joint communication during experimental arthritis. Arthritis Rheum. 2008;58:3090-3099
del Rey A, Wolff C, Wildmann J, Randolf A, Hahnel A, Besedovsky HO, Straub RH
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When immune-neuro-endocrine interactions are disrupted: experimentally induced arthritis as an example. Neuroimmunomodulation. 2010;17:165-168
del Rey A, Wolff C, Wildmann J, Randolf A, Straub RH, Besedovsky HO
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Inadequate corticosterone levels relative to arthritic inflammation are accompanied by altered mitochondria/cholesterol breakdown in adrenal cortex: a steroid-inhibiting role of IL-1β in rats. Ann Rheum Dis. 2015;74:1890-1897
Wolff C, Krinner K, Schroeder JA, Straub RH
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Mimicking disruption of brain-immune system-joint communication results in collagen type II-induced arthritis in non-susceptible PVG rats. Molecular & Cellular Endocrinol 2015
Wolff C, Straub RH, Hahnel A, Randolf A, Wildmann J, Besedovsky HO, del Rey A
