Macrophages regulate the clearance of living cells by calreticulin

Abstract

Recently, Feng, Weissman and colleagues demonstrated that activated macrophages secrete calreticulin (CRT), which binds to the surface of viable target cells and marks them for removal by programmed cell phagocytosis (PrCP)1. CRT is one of the ‘eat me’ signals, which is often thought to localize in the lumen of the endoplasmic reticulum (ER), but was also found on the plasma membrane of apoptotic cancerous cells (Fig. 1), where it is believed to function as an ‘eat me’ signal2 and a damage-associated molecular pattern (DAMP) responsible for the immunogenicity of apoptotic cancerous cells3. Remarkably, some viable cells also expose CRT but are apparently protected from engulfment. One of the mechanisms for this protection is related to repelling signals mediated by so-called ‘don’t eat me’ signals concurrently expressed on the cells, such as CD31, CD200 and CD474. Importantly, clearance of viable cells has been recently recognized in a few contexts, and it has been intriguing, in part due to the lack of an obvious mechanism, and also for its relevance. Some examples of reported live cell clearance include suicidal emperipolesis5, entosis6, phagoptosis7, and cell cannibalism8. However, the source and specific role of CRT in the engulfment of viable cells and the binding moiety on the surface of viable cells have not been known yet. Open in a separate window Fig. 1 Mechanisms of recognition of viable (a) and apoptotic (b) cells. a A soluble calreticulin (sCRT) secreted by activated macrophages is capable of binding to asialoglycans on viable target cells, depending on their developmental or damage state, which in turn, marks them for uptake. Neuraminidase-4 is one enzyme that could be involved in the generation of cell surface asialoglycans that bind sCRT. The cell-surface mCRT on the target cells can now interact with CD91, which is also known as low-density lipoprotein receptor-related protein 1 (LRP1). b CRT and CD91 have also been linked to immunogenic apoptotic cell death. On the surface of apoptotic cells expose phosphatidylserine (PS) and mCRT that function as “eat me” signals. The mCRT expression is particularly linked to cell death induced by agents that are known to induce immunogenic forms of apoptotic cell death. The expression of “don’t eat me” signals (e.g., CD47) on the apoptotic cells is either reduced or its location modified. Many membrane-bound receptors for PS have been reported, including those that bind PS directly or indirectly via bridging molecules. mCRT can bind CD91 on the phagocyte. The authors thank Servier for the figures that were produced using Servier Medical Art (www.servier.com)