Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages

Guang Sheng Ling,Jason Bennett,Philip R Taylor,Diane Scott,Marta Szajna,Liliane Fossati-Jimack,Kevin J Woollard,Guido Franzoso,H Terence Cook,Marina Botto

doi:10.1038/ncomms4039

Guang Sheng Ling, Jason Bennett + Show 8 more

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https://doi.org/10.1038/ncomms4039

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Journal: Nature Communications	Publication Date: Jan 15, 2014
Citations: 138	License type: CC BY 3.0

Affiliation: Hammersmith Hospital, Cardiff University

Abstract

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. However, the molecule(s) that confer these cell-type-specific LPS-induced effects remain poorly understood. Here we report that the integrin αM (CD11b) positively regulates LPS-induced signalling pathways selectively in myeloid dendritic cells but not in macrophages. In dendritic cells, which express lower levels of CD14 and TLR4 than macrophages, CD11b promotes MyD88-dependent and MyD88-independent signalling pathways. In particular, in dendritic cells CD11b facilitates LPS-induced TLR4 endocytosis and is required for the subsequent signalling in the endosomes. Consistent with this, CD11b deficiency dampens dendritic cell-mediated TLR4-triggered responses in vivo leading to impaired T-cell activation. Thus, by modulating the trafficking and signalling functions of TLR4 in a cell-type-specific manner CD11b fine tunes the balance between adaptive and innate immune responses initiated by LPS.

Highlights

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity
LPS responses depend on a membranespanning complex formed by TLR4/MD-2, several molecules have been shown to act as co-receptors and/or accessory molecules and to regulate both positively and negatively LPS sensing/signalling[8]
We demonstrate that CD11b can serve as a positive regulator of both TLR4-induced signalling pathways only on myeloid-derived Dendritic cells (DCs); it is dispensable in fully differentiated MFs

Summary

Introduction

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. Dendritic cells (DCs) and macrophages (MFs) arise from common myeloid precursors and share the ability to sample the tissue environment but have distinct effector functions[2] Both types of cell sense microbes through pattern-recognition receptors, which initiate downstream signalling events[3]. TLR4 is internalized into the endosome where a MyD88-independent pathway is triggered These second signalling events are controlled by the adaptor molecules, TRAM (TRIF-related adaptor molecule) and TRIF (TIR-domain-containing adapter-inducing interferon-b)[5], which activate Interferon (IFN) Regulatory Factor-3 (IRF3) leading to the subsequent production of type I IFNs and CCL5 (RANTES)[6,7]. CR3 activation is mediated by conformational changes often referred to as the ‘inside-out’ and ‘outside-in’ signalling pathways[10]

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