Lipedema – lack of evidence for the involvement of tyrosine kinases.

Lipedema is a chronic disorder characterized by abnormal distribution of subcutaneous adipose tissue on the proximal extremities, pain and capillary fragility. Its etiology is unknown but in analogy to central obesity, chronic low-level inflammation in adipose tissue has been suggested. There seems to be an increased propagation of pre-adipocytes into mature adipocytes contributing to the massive enlargement of subcutaneous adipose tissue. We investigated whether tyrosine kinases might be involved. Proteins from adipose tissue harvested during microcannular tumescent liposuction in lipedema and in lipomas were subjected to 10% polyacrylamide-gel, transferred to a polyvinylidenfluorid membrane and immunoblotted with indicated P-Tyr-100 antibody followed by enhanced chemiluminescence reaction. A survey of all blots did not reveal tyrosine-phosphorylated proteins with a molecular weight >100 kD in lipedema tissue and controls. These investigations suggest absence of activated growth factor receptors. Some signals indicating unspecific tyrosine-phosphorylation of smaller proteins were detected in tissue of both lipedema patients and controls. The present data suggest that there is no enduring activation of tyrosine kinase pathways of adipogenesis in lipedema as in lipoma controls.

The fifth dimension of innate immunity.

Innate immunity has evolved as a first line defense against invading pathogens. Cellular and humoral elements of the innate immune system detect infectious parasites, initiate inflammatory resistance reactions and finally contribute to the elimination of the invaders. Repeated attacks by pathogenic agents induce adaptive responses of the innate immune system. Typically, reapplication of pathogens provokes tolerance of the affected organism. However, also stimulatory effects of primary infections on subsequent innate immune responses have been observed. The present overview touches an undervalued aspect in the innate immune response: Its pronounced dependency on pathogen load. In addition to localization and timing of innate immune responses the pathogen dose dependency might be considered as a "fifth dimension of innate immunity". Experimental results and literature data are presented proposing a hormetic reaction pattern of innate immune cells depending on the dose of pathogens.

Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP.

Microglial phagocytosis plays a key role in neuroprotective and neurodegenerative responses of the innate immune system in the brain. Here we investigated the regulatory function of phosphoinositide 3-kinase γ (PI3Kγ) in phagocytosis of bacteria and Zymosan particles by mouse brain microglia in vitro and in vivo. Using genetic and pharmacological approaches our data revealed PI3Kγ as an essential mediator of microglial phagocytosis. Unexpectedly, microglia expressing lipid kinase deficient mutant PI3Kγ exhibited similar phagocytosis as wild-type cells. These data suggest kinase-independent stimulation of cAMP phosphodiesterase activity by PI3Kγ as a crucial mediator of phagocytosis. In sum our findings indicate PI3Kγ-dependent suppression of cAMP signaling as a critical regulatory element of microglial phagocytosis.