CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells.

Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonself-pathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNase-treated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.

"Eat me" and "don't eat me" signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system.

A full innate immune system (e.g. complement system, scavenger receptors, Toll-like receptors (TLR)) has been described in the CNS and is thought to be an extremely efficient army designed to fight against invading pathogens and toxic cell debris such as apoptotic cells and amyloid fibrils. The binding of soluble or secreted innate immune molecules on pathogen-associated molecular patterns (PAMPs) as well as apoptotic cell-associated molecular patterns (ACAMPs) provide several "eat me" signals to promote the safe disposal of the intruders by professional and amateur phagocytes. These patterns are deciphered by receptors (pattern recognition receptors, PRRs; e.g. CR3) that control phagocytosis and associated inflammatory response depending on the meaning of these signals. Importantly, in order to avoid excessive collateral damage of surrounding cells, it is increasingly evident that "don't eat me" signals (coined herein as self-associated molecular patterns, SAMPs; e.g. complement regulatory proteins, CD200) are of paramount importance to signal a robust anti-inflammatory response and promote tissue repair. Further knowledge of the innate immune response in the CNS will greatly help to delineate the novel therapeutic routes to protect from CNS inflammation and neurodegeneration.

Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection.

The complement system is an essential effector of the humoral and cellular immunity involved in cytolysis and immune/inflammatory responses. Complement participates in host defense against pathogens by triggering the formation of the membrane attack complex. Complement opsonins (C1q, C3b, and iC3b) interact with surface complement receptors to promote phagocytosis, whereas complement anaphylatoxins C3a and C5a initiate local inflammatory responses that ultimately contribute to the protection and healing of the host. However, activation of complement to an inappropriate extent has been proposed to promote tissue injury. There is now compelling evidence that complement activation in the brain is a double-edged sword in that it can exert beneficial or detrimental effects depending on the pathophysiological context. This review focuses on the roles of the complement system in the pathogenesis of acute brain injury (cerebral ischemia and trauma) and chronic neurodegeneration (Alzheimer's disease). Because many effects of the complement appear to promote neuronal survival and tissue remodeling, directing activation of the complement system in the brain may provide a better therapeutic rationale than inhibiting it.