Sex specificities in the modulatory action of noradrenaline on cd4+ t lymphocytes in experimental autoimmune encephalomyelitis model

[I. M. Prijić]

126 str.

Biologija - Imunobiologija / Biology -Immunobiology

Pretpostavljeno je da disfunkcija u, suštinski polno dimorfnoj, aktivnosti simpatičkog nervnog sistema (SNS) doprinosi patogenezi eksperimentalnog autoimunskog encefalomijelitisa (EAE). Ova hipoteza je testirana ispitivanjem uticaja farmakoloških manipulacija delovanjem noradrenalina (krajnji medijator SNS), na CD4+ T-limfocite u drenirajućim limfnim čvorovima (dLČ) i na inflamaciju posredovanu CD4+ T-limfocitima u kičmenoj moždini (KM) ženki i mužjaka pacova soja Dark Agouti (DA) kod kojih je indukovan EAE. Kako je blokada β-adrenalinskih receptora (AR), ali ne i α-AR, pokazala polno dimorfne efekte, istraživanje je bilo usmereno na efekte blokade β-AR. In vivo blokada β-AR propranololom (PROP) u peri-induktivnoj/induktivnoj fazi EAE smanjila je proliferaciju CD4+ T-limfocita i njihovu diferencijaciju u potencijalno patogene ćelije u dLČ nezavisno od pola. Ovakav efekat je rezultanta polno-specifičnog (izraženijeg kod mužjaka) (a) inhibitornog delovanja PROP na migraciju antigen-prezentujućih ćelija (APĆ) in vivo, i (b) stimulativnog efekta PROP na ekspresiju IL-1β i IL-23 u APĆ, te proliferaciju i diferencijaciju CD4+ limfocita u potencijalno visoko patogene IL-17+GM-CSF+ ćelije, uočenog in vitro. Tretman PROP u efektorskoj fazi EAE je stimulisao razvoj anti-inflamatornog fenotipa mikroglije, direktnom ili indirektnom (stimulacijom CX3CL1/CX3CR1 signalnog puta) transkripcionom aktivacijom Nrf2/HO-1 osovine, i inhibitornim delovanjem na komponente IL-6/Stat3 osovine (delom kroz ushodnu regulaciju ekspresije Socs3), i time smanjio infiltraciju KM mijeloidnim ćelijama i CD4+ T-limfocitima, i njihovu reaktivaciju i diferencijaciju u IL-17+GM-CSF+ ćelije. Ovi efekti PROP su bili izraženiji kod mužjaka nego ženki pacova, objašnjavajući, delom, izraženije smanjenje težine EAE kod pacova muškog pola.

It has been hypothesized that dysfunction in, basically sexually dimorphic, activity of the sympathetic nervous system (SNS) contributes to the pathogenesis of experimental autoimmune encephalomyelitis (EAE). To test the hypothesis, the influence of pharmacological manipulations with action of noradrenaline (end point mediator of the SNS) on CD4+ T-cells in draining lymph nodes (dLNs) and CD4+ T-cell-mediated inflammation in the spinal cord (SC) of female and male Dark Agouti (DA) rats immunized for EAE was investigated. Since blockade of β-adrenoceptors (ARs), but not α-ARs, produced sexually dimorphic effects, study was focused on the effects of β-AR blockade. In vivo blockade of β-AR with propranolol (PROP) over the peri-inductive/inductive phase of EAE decreased dLN CD4+ T-cell proliferation and differentiation into potentially pathogenic cells regardless of sex. This reflected the net effect of sex-specific (greater in males) PROP-induced (a) inhibition of antigen presenting cell (APC) migration in vivo, and (b) stimulation of IL-1β and IL-23 expression in APCs, and CD4+ cell proliferation and differentiation into potentially highly pathogenic IL-17+GM-CSF+ cells, observed in vitro. PROP treatment in the effector phase of EAE promoted anti-inflammatory phenotype of microglia by direct or indirect (via CX3CL1/CX3CR1 pathway stimulation) transcriptional activation of Nrf2/HO-1 axis and inhibitory action on IL-6/Stat3 axis components expression (partly via upregulation of Socs3), and thereby decreased SC infiltration with blood-borne myeloid cells and CD4+ T-cells, and their reactivation and differentiation into IL-17+GM-CSF+ cells. Effects of PROP were more prominent in male than female rats, partly explaining greater decrease in EAE severity in PROP-treated males.

noradrenalin, β-AR, tirozin-hidroksilaza, EAE, DA pacovi, polni dimorfizam, Th17 limfociti, antigen-prezentujuće ćelije, mikroglija, monociti

noradrenaline, β-AR, tyrosine hydroxylase, EAE, DA rats, sexual dimorphism, Th17 lymphocytes, antigen presenting cells, microglia, monocytes

577.27:616-097(043.3)

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