CD14 but not MD2 transmit signals from DAMP

Area of Science:

• Immunology
• Molecular Biology

Background:

• Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate immune cells via pattern recognition receptors (PRRs), including Toll-like receptors (TLRs).
• TLR complexes like TLR4-CD14-MD2 and TLR2-CD14 are crucial for recognizing lipopolysaccharide (LPS) and peptidoglycan (PG).
• DAMPs can also activate TLR2 or TLR4 pathways, necessitating a clearer understanding of receptor complex roles.

Purpose of the Study:

• To dissect the roles of CD14 and MD2 in receptor complexes responding to DAMPs (necrotic cells) and PAMPs (LPS, PG).
• To investigate the involvement of CD14 and MD2 in NF-kappaB activation and cytokine production.

Main Methods:

• Investigated NF-kappaB activation in response to necrotic cells, LPS, and PG using various receptor complex configurations.
• Compared immune responses in CD14-positive and CD14-negative mice.
• Utilized microarray analysis to assess gene regulation in peritoneal cells.

Main Results:

• CD14 significantly contributed to NF-kappaB activation by necrotic cells, independent of TLR2.
• MD2 showed no significant role in NF-kappaB activation by necrotic cells but was crucial for PG recognition with TLR2-CD14.
• CD14-negative mice exhibited delayed IL12p40 production in response to necrotic cells, and pro-inflammatory gene expression was CD14-dependent.

Conclusions:

• CD14 functions as a universal adaptor for both DAMPs and PAMPs, recognizing necrotic cells, LPS, PG, apoptotic cells, and lipids.
• MD2 specifically recognizes exogenous PAMPs when complexed with TLR2-CD14 or TLR4-CD14.
• MD2 plays a critical role in discriminating between DAMP and PAMP signaling pathways.