IRE1 as a regulator of apoptotic cell engulfment in macrophages.

Macrophages (Macs) in our body are facing the daunting task of adapting their own metabolism to the influx of excess metabolites from the corpses they engulf. How this is achieved remains as yet largely unanswered. Over the past few years several individual key components have been identified, but whether there is an overarching pathway orchestrating this response remains unclear. Previous data from my host lab revealed that in dendritic cells (DCs), Inositol Requiring Enzyme 1 (IRE1), an ER based sensor of the unfolded protein response (UPR), plays a crucial role in apoptotic cell engulfment and appears triggered upon engulfment, likely by an influx in cholesterol. The UPR is traditionally associated with secretory cells to cope with increased demand in protein folding. We found that in some immune cell types, like DCs and Macs, the IRE1 pathway is highly active in steady state, and postulated functions that extend beyond its role in folding. The function of IRE1 in macrophages is hardly known. We hypothesize that -similar as in DCs-, the ER and IRE1 might play a central role in sensing apoptotic cell engulfment and coordinating ensuing metabolic responses. To approach this question, we generated macrophage specific knockout mice for IRE1 and XBP1, its downstream transcription factor, and will study the function and phenotype of tissue Macs therein. We will assess engulfment capacity and gene modules affected by IRE1, but will also explore potential autoimmune responses.