Phagocytosis of Apoptotic Cells by Macrophages Induces Novel Signaling Events Leading to Cytokine-Independent Survival and Inhibition of Proliferation: Activation of Akt and Inhibition of Extracellular Signal-Regulated Kinases 1 and 2

Abstract

Recent evidence indicates that phagocytic clearance of apoptotic cells, initially thought to be a silent event, can modulate macrophage (Mφ) function. We show in this work that phagocytic uptake of apoptotic cells or bodies, in the absence of serum or soluble survival factors, inhibits apoptosis and maintains viability of primary cultures of murine peritoneal and bone marrow Mφ with a potency approaching that of serum-supplemented medium. Apoptotic uptake also profoundly inhibits the proliferation of bone marrow Mφ stimulated to proliferate by M-CSF. While inhibition of proliferation is an unusual property for survival factors, the combination of increased survival and decreased proliferation may aid the Mφ in its role as a scavenger during resolution of inflammation. The ability of apoptotic cells to promote survival and inhibit proliferation appears to be the result of simultaneous activation of Akt and inhibition of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and ERK2 (ERK1/2). While several activators of the innate immune system, or danger signals, also inhibit apoptosis and proliferation, danger signals and necrotic cells differ from apoptotic cells in that they activate, rather than inhibit, ERK1/2. These signaling differences may underlie the opposing tendencies of apoptotic cells and danger signals in promoting tolerance vs immunity.

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

“…Wnt-3a and Wnt-10b represent canonical Wnt family members with well-established strong anabolic signaling in bone. Interestingly, recent studies demonstrated that macrophage-derived Wnt proteins are essential for tissue regeneration in kidney (30,31) and liver (32). In particular, phagocytosis of apoptotic debris was found to stimulate macrophage production of Wnt-3a, which mediated hepatocyte regeneration (32).…”

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

“…We found that CR3 ligation inhibited LPS-induced ERK1/2 phosphorylation (our unpublished data), and because ERK inhibition could only partially recapitulate CR3 effects (our unpublished data), we must hypothesize that other molecules are involved in CR3 signaling. Given that apoptotic cells affect other MAPK pathway molecules (45,46), future efforts will be directed toward studying these enzymes.…”

Recognition-dependent Signaling Events in Response to Apoptotic Targets Inhibit Epithelial Cell Viability by Multiple Mechanisms

“…In addition, the form of cell death is important. We have shown that the signaling events induced in responding cells by apoptotic versus necrotic targets are often diametrically opposed (3,5,17). The different responses to these two forms of cell death can serve as a "gauge" by which surrounding cells assess the overall severity of an environmental stress: sudden and catastrophic in the case of necrotic targets versus more gradual and potentially adaptable in the case of apoptotic targets.…”

“…To date, study of these effects has been largely focused on professional phagocytes, like macrophages (m). 2 For example, we have shown that apoptotic targets inhibit apoptosis and maintain the viability of primary m cultures even in the absence of serum or other survival factors (5).…”

“…This is accomplished through a variety of interconnected mechanisms. Notably, cells dying by apoptosis acquire new activities, both secreted and cell-associated, that enable them to modulate the function of interacting phagocytes (3)(4)(5)(6). Although the best known of these activities is anti-inflammatory (7)(8)(9)(10)(11)(12), apoptotic targets also affect other phagocyte functions related to innate and adaptive immunity, including antigen processing and presentation (13,14), expression of co-stimulatory activity for lymphocytes (15), and the recruitment and trafficking of immune cells (16).…”