Faculty Opinions recommendation of Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity.

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.

Download Full-text

Regulation of Adaptive Immunity by the Innate Immune System

Science ◽

10.1126/science.1183021 ◽

2010 ◽

Vol 327 (5963) ◽

pp. 291-295 ◽

Cited By ~ 1229

Author(s):

A. Iwasaki ◽

R. Medzhitov

Keyword(s):

Immune System ◽

Adaptive Immunity ◽

Innate Immune System ◽

Innate Immune

Download Full-text

Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation

Journal of Cell Science ◽

10.1242/jcs.115.12.2603 ◽

2002 ◽

Vol 115 (12) ◽

pp. 2603-2611 ◽

Cited By ~ 7

Author(s):

Martha Triantafilou ◽

Kensuke Miyake ◽

Douglas T. Golenbock ◽

Kathy Triantafilou

Keyword(s):

Lipid Rafts ◽

Lipid Raft ◽

Cell Activation ◽

Imaging Techniques ◽

Recognition System ◽

Innate Immune ◽

Membrane Microdomains ◽

Immune Recognition ◽

Cellular Activation ◽

Signalling Molecules

The plasma membrane of cells is composed of lateral heterogeneities,patches and microdomains. These membrane microdomains or lipid rafts are enriched in glycosphingolipids and cholesterol and have been implicated in cellular processes such as membrane sorting and signal transduction. In this study we investigated the importance of lipid raft formation in the innate immune recognition of bacteria using biochemical and fluorescence imaging techniques. We found that receptor molecules that are implicated in lipopolysaccharide (LPS)-cellular activation, such as CD14, heat shock protein(hsp) 70, 90, Chemokine receptor 4 (CXCR4), growth differentiation factor 5(GDF5) and Toll-like receptor 4 (TLR4), are present in microdomains following LPS stimulation. Lipid raft integrity is essential for LPS-cellular activation, since raft-disrupting drugs, such as nystatin or MCD, inhibit LPS-induced TNF-α secretion. Our results suggest that the entire bacterial recognition system is based around the ligation of CD14 by bacterial components and the recruitment of multiple signalling molecules, such as hsp70, hsp90, CXCR4, GDF5 and TLR4, at the site of CD14-LPS ligation, within the lipid rafts.

Download Full-text