C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells

TLDR

Removal of apoptotic cells is essential for tissue homeostasis, organogenesis, and immune regulation, and this clearance is mediated by recognition of apoptotic surface markers that trigger phagocytic uptake. The study demonstrates that C1q and mannose‑binding lectin bind apoptotic cells and stimulate their ingestion by ligating calreticulin (cC1qR) on phagocytes, which is linked to the endocytic receptor CD91. C1q and MBL engage apoptotic cells and, through binding to calreticulin on phagocytes, activate CD91‑mediated endocytosis. Ingestion via the calreticulin/CD91 pathway involves macropinocytosis, a primitive, nonselective uptake mechanism that enables C1q‑ and MBL‑enhanced engulfment of intact apoptotic cells, debris, and foreign organisms.

Abstract

Removal of apoptotic cells is essential for maintenance of tissue homeostasis, organogenesis, remodeling, development, and maintenance of the immune system, protection against neoplasia, and resolution of inflammation. The mechanisms of this removal involve recognition of the apoptotic cell surface and initiation of phagocytic uptake into a variety of cell types. Here we provide evidence that C1q and mannose binding lectin (MBL), a member of the collectin family of proteins, bind to apoptotic cells and stimulate ingestion of these by ligation on the phagocyte surface of the multifunctional protein, calreticulin (also known as the cC1qR), which in turn is bound to the endocytic receptor protein CD91, also known as the α-2-macroglobulin receptor. Use of these proteins provides another example of apoptotic cell clearance mediated by pattern recognition molecules of the innate immune system. Ingestion of the apoptotic cells through calreticulin/CD91 stimulation is further shown to involve the process of macropinocytosis, implicated as a primitive and relatively nonselective uptake mechanism for C1q- and MBL-enhanced engulfment of whole, intact apoptotic cells, as well as cell debris and foreign organisms to which these molecules may bind.