> A recent report showed that innate immune triggers (for example, Escherichia coli and Salmonella) induce LD formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins, such as cathelicidin (CAMP), kill bacteria8. We speculate that a similar programme can be triggered in human microglia exposed to Aβ, LPS and other innate immune activators and disrupt brain homeostasis. Protein aggregates found in other neurodegenerative diseases may trigger the LDAM state. For example, alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM36. Given that we recently identified that LDAM are abundant in the ageing mouse brain, LDAMs may also be triggered by hitherto unknown protein aggregates and innate immune activators which accumulate with age. Interestingly, the most enriched pathway in human LD-containing iMGs is ‘cellular senescence’, similar to lipid-laden ‘foamy macrophages’ in atherosclerosis which have a senescent phenotype and are drivers of pathology37. Perhaps in the natural ageing of various organs, LD-accumulating tissue-resident macrophages represent a general class of senescent myeloid cells which are drivers of tissue inflammation.
It could be a lot of things, and there might be multiple pathways that lead to this state.
> A recent report showed that innate immune triggers (for example, Escherichia coli and Salmonella) induce LD formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins, such as cathelicidin (CAMP), kill bacteria8. We speculate that a similar programme can be triggered in human microglia exposed to Aβ, LPS and other innate immune activators and disrupt brain homeostasis. Protein aggregates found in other neurodegenerative diseases may trigger the LDAM state. For example, alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM36. Given that we recently identified that LDAM are abundant in the ageing mouse brain, LDAMs may also be triggered by hitherto unknown protein aggregates and innate immune activators which accumulate with age. Interestingly, the most enriched pathway in human LD-containing iMGs is ‘cellular senescence’, similar to lipid-laden ‘foamy macrophages’ in atherosclerosis which have a senescent phenotype and are drivers of pathology37. Perhaps in the natural ageing of various organs, LD-accumulating tissue-resident macrophages represent a general class of senescent myeloid cells which are drivers of tissue inflammation.
It could be a lot of things, and there might be multiple pathways that lead to this state.
[1] https://www.nature.com/articles/s41586-024-07185-7#Sec6