BHLHE40 and BHLHE41 Deletion May Make Macrophages and Microglia More Efficient
Macrophages in the body and microglia in the brain are similar forms of innate immune cell, responsible for clearing metabolic waste, among other duties. A number of age-related conditions involve the growing incapacity of macrophages or microglia, their transition to inflammatory states, and inability to clear debris and waste as they should. Atherosclerosis, for example, is arguably a condition caused by macrophage dysfunction, in which macrophages fail to clear excess cholesterol from blood vessel walls. Neurodegenerative conditions such as Alzheimer's disease, on the other hand, are characterized by the presence of activated, senescent, and overly inflammatory microglia. Can these cells be made more resilient to the aged tissue environment, made less inflammatory, made better at the task of waste clearance? Perhaps, as the work here indicates.
Genetic and experimental evidence suggests that Alzheimer's disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, single cell RNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as disease-associated and lipid-associated cells, here DLAMs for brevity.
Using macrophage RNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40 and BHLHE41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.