MKK3 mediates inflammatory response through modulation of mitochondrial function

•Mitochondria are increasingly recognized as drivers of inflammatory responses.•We show that MAP kinase kinase 3 (MKK3) influences mitochondrial function and p38 and acts as a critical mediator of inflammation.•MKK3 deletion causes decreased production of ROS and reduction in NF-κB and caspase-1 activity leading to attenuated cytokine release after LPS stimulation.•MKK3 is a potential therapeutic target for treatment of inflammatory disorders such as sepsis.

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 smaller amounts of cytokines than wild type (WT) after lipopolysaccharide (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−/− BMDMs did not show a significant increase in cellular reactive oxygen species production or in mitochondrial superoxide 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), was lower in MKK3−/− BMDMs. p38 and JNK activation was 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 such as sepsis.

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