Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Abstract

Removal of cells dying by apoptosis is essential to normal development, maintenance of tissue homeostasis, and resolution of inflammation. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are high abundance pulmonary collectins recently implicated in apoptotic cell clearance in vitro. Other collectins, such as mannose-binding lectin and the collectin-like C1q, have been shown to bind to apoptotic cells and drive ingestion through interaction with calreticulin and CD91 on the phagocyte in vitro. However, only C1q has been shown to enhance apoptotic cell uptake in vivo. We sought to determine the relative importance of SP-A, SP-D, and C1q in pulmonary clearance of apoptotic cells using knockout and overexpressing mice, and to determine the role of calreticulin and CD91 in this process. SP-A, SP-D, and C1q all enhanced apoptotic cell ingestion by resident murine and human alveolar macrophages in vitro. However, only SP-D altered apoptotic cell clearance from the naive murine lung, suggesting that SP-D plays a particularly important role in vivo. Similar to C1q and mannose-binding lectin, SP-A and SP-D bound to apoptotic cells in a localized, patchy pattern and drove apoptotic cell ingestion by phagocytes through a mechanism dependent on calreticulin and CD91. These results suggest that the entire collectin family of innate immune proteins (including C1q) works through a common receptor complex to enhance removal of apoptotic cells, and that collectins are integral, organ-specific components of the clearance machinery.

Mannose‐binding lectin engagement with late apoptotic and necrotic cells

“…However, this leaves us with the obvious question, what kind of effector machinery does MBL utilize to remove apoptotic cells? Two recent studies have brought further insight to this question indicating that both C1q, SP-A, SP-D as well as MBL utilize the calreticulin/CD91 complex on phagocytes as acceptor site for sequestration of apoptotic material [9,16]. Consistent with these studies, we demonstrated that opsonization of apoptotic cells with MBL facilitated their uptake by macrophages.…”

Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity

“…In contrast, heat shock proteins binding to CD91 19,20 may interfere with phagocytosis of apoptotic cells. [21][22][23] In such a model, the result of heat [5][6][7][8][9]. These mice, along with untreated naïve mice were rechallenged with 2 Â 10 6 parental CMT93 s.c., and tumor growth followed for 60 days.…”

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

“…Human alveolar macrophages were isolated by bronchoalveolar lavage from patients with Global Initiative for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 COPD as described (31,45). The right middle lobe was lavaged with 100 ml of 0.9% saline solution at room temperature.…”