Cyclic Stretch Negatively Regulates IL-1β Secretion Through the Inhibition of NLRP3 Inflammasome Activation by Attenuating the AMP Kinase Pathway

Abstract

Macrophages are immune cells of hematopoietic origin that play diverse roles in host defenses and tissue homeostasis. In mechanical microenvironments, macrophages receive mechanical signals that regulate various cellular functions. However, the mechanisms by which mechanical signals influence the phenotype and function of macrophages in the process of inflammation have not yet been elucidated in detail. We herein examined the effects of cyclic stretch (CS) on NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation in J774.1, a murine macrophage cell line, and mouse primary bone marrow-derived macrophages. We showed that cyclic stretch inhibited adenosine triphosphate (ATP)-stimulated interleukin (IL)-1β secretion in lipopolysaccharide (LPS)-primed macrophages using ELISA and Western blot analyses. Cyclic stretch did not affect the degradation of the Inhibitor of κB or the nuclear translocation/transcriptional activity of nuclear factor (NF)-κB, suggesting that cyclic stretch-mediated inhibition was independent of the NF-κB signaling pathway. Consistent with these results, cyclic stretch did not affect the LPS-induced expression of inflammasome components, such as pro-IL-1β and NLRP3, which is known to require the activation of NF-κB signaling. We showed that the cyclic stretch-mediated inhibition of IL-1β secretion was caused by the suppression of caspase-1 activity. The addition of compound C, a specific inhibitor of adenosine monophosphate-activated protein kinase (AMPK), to LPS-primed macrophages inhibited IL-1β secretion as well as caspase-1 activation, suggesting that AMPK signaling is involved in ATP-triggered IL-1β secretion. Furthermore, the phosphorylation of AMPK induced by ATP in LPS-primed macrophages was significantly suppressed by cyclic stretch, indicating that cyclic stretch negatively regulates IL-1β secretion through the inhibition of caspase-1 activity by attenuating the AMPK pathway. Our results suggest that mechanical stress functions to maintain homeostasis through the prevention of excessive inflammasome activation in macrophages in mechanical microenvironments.

Mechanical regulation of macrophage function - cyclic tensile force inhibits NLRP3 inflammasome-dependent IL-1β secretion in murine macrophages

“…Therefore, the relationship between mechanical stress and inflammasome signaling is still unclear. Recently, we found that cyclic stretch suppresses the NLRP3 inflammasome in macrophages [51] and will introduce our new findings in the latter part of this paper (Fig. 2).…”

Cyclic Stretch Force Induces Periodontal Ligament Cells to Secrete Exosomes That Suppress IL-1β Production Through the Inhibition of the NF-κB Signaling Pathway in Macrophages

“…In the present study, we demonstrated for the first time that cyclic stretch induced PDL cells to secrete exosomes, which exhibited anti-inflammatory properties in macrophages. We previously reported that the exposure of LPS-primed macrophages to cyclic stretch inhibited IL-1β secretion by attenuating the AMP kinase pathway (45). Therefore, the NLRP3 inflammasomes of macrophages may be tightly regulated by multiple feedback systems that maintain immune/inflammatory homeostasis in periodontal tissue.…”

Local cyclical compression modulates macrophage functionin situand alleviates immobilization-induced muscle atrophy

“…Together with the resistance of gastrocnemius muscle of clodronate liposome-administered mice to hindlimb immobilization ( Figure 3A-C), mechanosensory function of macrophages recruited from circulating blood appears to be involved in tissue homeostasis. Whereas the decrease in MCP-1 expression in cultured macrophages by FSS relates to anti-inflammation, both pro-and anti-inflammatory effects of cyclical stretching of cultured macrophages have been reported [46,47]. Such variation might be due to the complexity of cyclical stretching, which is a combination of stretching and relaxation that can affect cellular signaling in opposite directions [48].…”