CaMK4 Promotes Acute Lung Injury Through NLRP3 Inflammasome Activation in Type II Alveolar Epithelial Cell

Abstract

BackgroundType II alveolar epithelial cell (AEC II), in addition to its roles in maintaining lung homeostasis, takes an active role in inflammatory response during acute lung injury (ALI). Ca2+/calmodulin-dependent protein kinase IV (CaMK4) activated by Ca2+/calmodulin signaling, has been implicated in immune responses. This study was to investigate the roles of CaMK4 in the development of ALI and the underlying mechanisms.MethodsCaMK4 inhibitor KN-93 was used to investigate the effects of CaMK4 on NLRP3 inflammasome activation. The effects of KN-93 on disease development of lipopolysaccharide (LPS)-induced ALI were also evaluated. The role of CaMK4 on NLRP3 inflammasome activation was explored in human AEC II cell line A549 using KN-93 or CaMK4 siRNA. NLRP3 inflammasome activation was measured by histology immunofluorescence and Western blot. IL-1β and IL-18 were measured by ELISA.ResultsPhosphorylation of CaMK4 and the expression of NLRP3 and Caspase-1 p20 were increased in the lungs of LPS-induced ALI mice, which was suppressed by KN-93 as measured by Western blot. Further, the activation of NLRP3 inflammasome was detected in AEC II from patients with acute respiratory distress syndrome (ARDS) and LPS-induced ALI mice. In vitro, inhibition or silencing CaMK4 in AEC II significantly inhibited NLRP3 inflammasome activation, resulting in reduced IL-1β production. The inhibition of NLRP3 inflammasome and decreased IL-1β/IL-18 production by KN-93 led to reduced inflammatory infiltration and ameliorated lung injury in LPS-induced ALI mice.ConclusionCaMK4 controls the activation of NLRP3 inflammasome in AEC II during LPS-induced ALI. CaMK4 inhibition could be a novel therapeutic approach for the treatment of ALI.

κ-Opioid Receptor Agonist U50448H Protects Against Acute Lung Injury in Rats with Cardiopulmonary Bypass via the CAP-NLRP3 Signaling Pathway

“…Our results unraveled that U50448H could downregulate the C and N terminals of GSDMD, NLRP3, ASC, pro-caspase-1, and pro-IL-1 β , as well as block cell pyroptosis, indicating the repressive effects of U50448H on NLRP3 inflammasome-induced cell pyroptosis during ALI secondary to CPB. This is probably because NLRP3 can manipulate the production of proinflammatory cytokines, which maintains the accumulation of inflammatory factors to a certain extent by regulating extracorporeal circulation and diminishes the occurrence of inflammatory diseases [ 35 ]. The research of Zhou et al validated that miR-495 attenuates cardiac microvascular endothelial injury and represses inflammatory cells by negatively modulating the expression of the NLRP3 inflammatory signaling pathway and reducing the levels of proinflammatory factors (TNF-a, IL-6, and IL-LP) in alveolar macrophages.…”

Garlic oil supplementation blocks inflammatory pyroptosis-related acute lung injury by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation

“…The production of mature forms of IL-1β and IL-18 depends on NLRP3 inflammasome activation, which is potentially responsible for ALI development [ 42 ]. The marked activation of the NF-κB signaling pathway, which is involved in the transcriptional regulation of NLRP3 inflammasome activation and in the production of IL-6, TNF-α, pro-IL-1β, and pro-IL-18, is also closely related to LPS-induced ALI [ 43 ].…”

“…The production of mature forms of IL-1β and IL-18 depends on NLRP3 inflammasome activation, which is potentially responsible for ALI development [42].…”

Acute Lung Injury and the NLRP3 Inflammasome

“…The drug KN-93, a CaMK4 inhibitor, can effectively improve ALI by inhibiting NLRP3 inflammasome activation. 119 Thus, inhibiting CaMK4 could represent a new approach for treating ALI.…”

“…Inhibiting the NF-kB Pathway Propofol [80,81] Metformin [82][83][84][85][86] Glibenclamide [87] Berberine [88][89][90][91] Glycyrrhizic acid [93][94][95][96] Isochlorogenic acid A [97] Pterin [98] Hederasaponin-C [99] Inhibiting the Excessive Production of ROS Emodin [100][101][102] Honokiol (HKL) [105] Oridonin (Ori) [106,107] Melatonin [108] Hydnocarpin D [109] Isoorientin [110] Citrulline [111] Glycyrrhizic acid [95] Inhibiting Mitochondrial Autophagy Sestrin2 (Sesn2) [113][114][115] Inhibiting Ion Channels KN-93 [119] Inhibiting…”