Map3k8 Modulates Monocyte State and Atherogenesis in ApoE ^−/− Mice

Cell Death in the Vessel Wall

“…However, compared to macrophages, the role for apoptosis of monocytes in the development of atherosclerosis is less well understood. A recent report revealed that in circulating pro-atherogenic monocytes, TLR signaling via the kinase Map3k8 renders monocytes resistant to apoptosis and when Map3k8 is deleted in hemotapoietic cells, atherosclerotic lesions are small due to high rates of monocyte apoptosis 63 . Although the endogenous regulators of monocyte apoptosis during atherosclerotic lesion formation have not been fully elucidated, this study suggests that monocyte-targeting therapies may be of therapeutic use.…”

Tumor Progression Locus 2 in Hepatocytes Potentiates Both Liver and Systemic Metabolic Disorders in Mice

“…The serine/threonine kinase, TPL2, plays an important role in innate and adaptive immunity and has emerged as a potentially interesting treatment target in various diseases with an inflammatory component . However, the regulatory effect of TPL2 on the development of NAFLD was largely unknown.…”

“…Tumor progression locus 2 (TPL2), also known as COT and MAP3K8, is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the function of different cell types. (5)(6)(7)(8) Accumulating evidence indicates that TPL2 is a drugable target in several inflammatory disease, for example, atherosclerosis, (9) cancer, (10) and acetaminophen-induced liver sterile inflammation. (11) Chronic low-grade inflammation is closely related to and may underlie the etiology and progression of NAFLD and its complications.…”

Monocytosis, Hypercholesterolemia, and the Kinase That Binds Them

“…Accumulation of cells in the growing atheroma depends on an arithmetic that must consider monocyte production, recruitment, macrophage differentiation and proliferation, death, and perhaps exit. From Sanz-Garcia et al, 9 it was not entirely clear whether Map3k8 deficiency had a dramatic effect on factors outside of CCR2 expression and Ly-6C high monocyte recruitment, but shifting the therapeutic focus from controlling local plaque responses to regulating upstream processes is worth evaluating.…”

“…Sanz-Garcia et al 9 focus on one such kinase, Map3k8, and identify how it can be targeted to alter monocyte biology and atherosclerosis.…”