TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism

Abstract

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.

Isoforskolin and forskolin attenuate lipopolysaccharide‐induced inflammation through TLR4/MyD88/NF‐κB cascades in human mononuclear leukocytes

“…In the present study, our results showed that LPS treatment increased the protein levels of TLR4, MyD88, and NF‐κB in human MLs. This result was similar with previous research (He et al, ) and further demonstrated that LPS signaled via TLR4 and MyD88 activated NF‐κB in anti‐inflammatory reaction. And our previous study also showed that ISOF can attenuate inflammation in BEAS‐2B induced by LPS through down‐regulating protein expression of TLR4, MyD88, and NF‐κB (this manuscript is under review now).…”

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…129,130 In addition to a set of immunological strategies mediated by response of M1 macrophages, TLR4 recognizes LPS, one of the major components produced by gram-negative bacteria, which activates NF-κB, AP1, and the production of TNF-α, IL-1β, IL-6, and IFN-γ ( Figure 2). [131][132][133] As an alternative pathway, M2 macrophages respond to stimulation by IL-4, IL-10, or IL-13 to mediate the development of the repair phenotype. By binding to their respective receptors, these cytokines can trigger activation of repair signaling cascades that modulate the activation and phosphorylation of JAK1-3, STAT3, STAT6, peroxisome proliferator-activated receptor γ (PPARγ) or phosphoinositide 3-K (PI3K) in order to induce production of Arg1, CD206, chitinase-like 3 (Chi313), reticulon-like A (Rtnla), TGF-β, NOS2, IL-4Rα, and IL-1Rα ( Figure 2).…”

Editorial: Therapeutics for acute lung injury: time to call in the DRs?

“…In line with the previous data presented in this paper, fenoldopam and another known AMPK activator, metformin, both prevented TNF-a release by the macrophages. As lung macrophages are known producers of IL-1b in response to LPS stimulation [6], these results suggest a positivefeedback loop initiated by this paracrine cross-talk ( Fig. 1).…”