LPS-Mediated Transcriptional Changes in Myeloid Lineage Cells: Macrophages and Osteoclasts

The NLRP3 inflammasome is a key driver of bone resorption in various inflammatory conditions, ranging from low-grade to high-grade inflammation. This bone-resorptive activity is mediated by osteoclasts (OCs), which differentiate from macrophages upon exposure to RANKL. While the non-autonomous effects of the inflammasome on the osteoclast lineage are well characterized, its cell-intrinsic (autonomous) role within these cells remains poorly understood. To address this knowledge gap, we treated mouse bone marrow-derived macrophages (BMDMs) with RANKL and monitored NLRP3 expression during osteoclastogenesis. Surprisingly, NLRP3 expression progressively declined as cells differentiated into osteoclasts, but was restored upon LPS priming. When OC cultures were exposed to LPS followed by nigericin to assess NLRP3 inflammasome activation, we observed robust inflammasome assembly in undifferentiated BMDMs, as expected. However, this response was absent in mature OCs and their lineage-committed precursors. To uncover the mechanisms underlying this suppression of NLRP3 activation during differentiation, we performed transcriptomic analysis across the macrophage-to-osteoclast transition, aiming to identify regulatory genes and pathways that may inhibit inflammasome assembly in OCs