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.