IL-1 receptor activation undermines respiratory motor plasticity after systemic inflammation

Abstract

Inflammation undermines respiratory motor plasticity, yet we are just beginning to understand the inflammatory signaling involved. Because interleukin-1 (IL-1) signaling promotes or inhibits plasticity in other central nervous system regions, we tested the following hypotheses: 1) IL-1 receptor (IL-1R) activation after systemic inflammation is necessary to undermine phrenic long-term facilitation (pLTF), a model of respiratory motor plasticity induced by acute intermittent hypoxia (AIH), and 2) spinal IL-1β is sufficient to undermine pLTF. pLTF is significantly reduced 24 h after lipopolysaccharide (LPS; 100 μg/kg ip, 12 ± 18%, n = 5) compared with control (57 ± 25%, n = 6) and restored by peripheral IL-1R antagonism (63 ± 13%, n = 5, AF-12198, 0.5 mg/kg ip, 24 h). Furthermore, acute, spinal IL-1R antagonism (1 mM AF-12198, 15 μl it) restored pLTF (53 ± 15%, n = 4) compared with LPS-treated rats (11 ± 10%; n = 5), demonstrating IL-1R activation is necessary to undermine pLTF after systemic inflammation. However, in healthy animals, pLTF persisted after spinal, exogenous recombinant rat IL-1β (rIL-1β) (1 ng ± AIH; 66 ± 26%, n = 3, 10 ng ± AIH; 102 ± 49%, n = 4, 100 ng + AIH; 93 ± 51%, n = 3, 300 ng ± AIH; 37 ± 40%, n = 3; P < 0.05 from baseline). In the absence of AIH, spinal rIL-1β induced progressive, dose-dependent phrenic amplitude facilitation (1 ng; −3 ± 5%, n = 3, 10 ng; 8 ± 22%, n = 3, 100 ng; 31 ± 12%, P < 0.05, n = 4, 300 ng; 51 ± 17%, P < 0.01 from baseline, n = 4). In sum, IL-1R activation, both systemically and spinally, undermines pLTF after LPS-induced systemic inflammation, but IL-1R activation is not sufficient to abolish plasticity. Understanding the inflammatory signaling inhibiting respiratory plasticity is crucial to developing treatment strategies utilizing respiratory plasticity to promote breathing during ventilatory control disorders.NEW & NOTEWORTHY This study gives novel insights concerning mechanisms by which systemic inflammation undermines respiratory motor plasticity. We demonstrate that interleukin-1 signaling, both peripherally and centrally, undermines respiratory motor plasticity. However, acute, exogenous interleukin-1 signaling is not sufficient to undermine respiratory motor plasticity.