MKK3 mediates inflammatory response through modulation of mitochondrial function

Abstract

Mitochondria are increasingly recognized as drivers of inflammatory responses. MAP kinase kinase 3 (MKK3), a dual-specificity protein kinase, is activated in inflammation and in turn activates p38 MAP kinase signaling. Here we show that MKK3 influences mitochondrial function and acts as a critical mediator of inflammation. MKK3 deficient (MKK3−/−) mice and bone marrow derived macrophages (BMDMs) secreted less cytokines than wild type (WT) after LPS exposure. There was improved mitochondrial function, as measured by basal oxygen consumption rate, mitochondrial membrane potential, and ATP production, in MKK3−/− BMDMs. After LPS exposure, MKK3−/− BMDM did not show significant increase in cellular reactive oxygen species (ROS) production as well as mitochondrial superoxide (MitoSOX) compared to WT. Activation of two important inflammatory mediators i.e. the nuclear translocation of NF-κB and caspase-1 activity (a key component of the inflammasome), were lower in MKK3−/− BMDMs. p-38 and JNK activation were lower in MKK3−/− BMDMs compared to WT after exposure to LPS. Knockdown of MKK3 by siRNA in wild type BMDMs improved mitochondrial membrane potential, reduced LPS induced caspase-1 activation and attenuated cytokine secretion. Our studies establish MKK3 as a regulator of mitochondrial function and inflammatory responses to LPS and suggest that MKK3 may be a therapeutic target in inflammatory disorders like sepsis.

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

“…Mice that are negative for MKK3 (the upstream effector of p38) exhibited reduced NF-κB and inflammasome activity in response to LPS. In the normal setting, mitochondrial ΔΨm is reduced, mtROS is elevated, and ATP levels fall upon LPS treatment (Srivastava et al, 2015). MKK3 knockout animals are protected from loss of ΔΨm suggesting the activation of p38 MAP kinase pathway elicits inflammatory signals by potentiating mitochondrial dysfunction to engage inflammatory signaling.…”

Warburg revisited: lessons for innate immunity and sepsis

“…In line with this concept, a recent study has shown that pyruvate kinase M2- HIF-1α mediated Warburg effect drives mortality in sepsis (Yang et al, 2014 ). Our data on macrophages indicates that preservation of mitochondrial function under inflammatory conditions leads to attenuated cytokine responses (Srivastava et al, 2015 ). The mechanism by which metabolic switching regulates inflammatory processes is a novel and promising area of research.…”

Proteomics data on MAP Kinase Kinase 3 knock out bone marrow derived macrophages exposed to cigarette smoke extract

“…Proteomic characterization of the effect of MKK3 deletion in bone marrow derived macrophages (BMDM), which provides data on MAP kinase signaling targets [2], [3], [4], [5], [6], [7].The BMDM proteomics data (total and phospho) has been presented which can be used as a reference for other inflammatory signaling molecules in MAP kinase pathway.The major canonical pathways affected after cigarette smoke in WT and MKK3 deleted BMDM are presented and can be utilized to interrogate the role of MAP kinases in other signaling schemes in cigarette smoke induced injury.…”

“…Proteomic characterization of the effect of MKK3 deletion in bone marrow derived macrophages (BMDM), which provides data on MAP kinase signaling targets [2], [3], [4], [5], [6], [7].…”