The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria

Abstract

Pattern recognition receptors (PRRs) play an essential role in a macrophage's response to mycobacterial infections. However, how these receptors work in concert to promote this macrophage response remains unclear. In this study, we used bone marrow-derived macrophages isolated from mannose receptor (MR), complement receptor 3 (CR3), MyD88, Toll-like receptor 4 (TLR4), and TLR2 knockout mice to examine the significance of these receptors in mediating a macrophage's response to a mycobacterial infection. We determined that mitogenactivated protein kinase (MAPK) activation and tumor necrosis factor-␣ (TNF-␣) production in macrophage infected with Mycobacterium avium or M smegmatis is dependent on myeloid differentiation factor 88 (MyD88) and TLR2 but not TLR4, MR, or CR3. Interestingly, the TLR2-mediated production of TNF-␣ by macrophages infected with M smegmatis required the ␤-glucan receptor dectin-1. A similar requirement for dectin-1 in TNF-␣ production was observed for macrophages infected with M bovis Bacillus Calmette-Guerin (BCG), M phlei, M avium 2151-rough, and M tuberculosis H37Ra. The limited production of TNF-␣ by virulent M avium 724 and M tuberculosis H37Rv was not dependent on dectin-1. Furthermore, dectin-1 facilitated interleukin-6 (IL-6), RANTES (regulated on activation, normal T expressed and secreted), and granulocyte colony-stimulating factor (G-CSF) production by mycobacteriainfected macrophages. These are the first results to establish a significant role for dectin-1, in cooperation with TLR2, to activate a macrophage's proinflammatory response to a mycobacterial infection. IntroductionThe immune system has the complex task of separating friend from foe. To accomplish this mission, the immune system has evolved receptors that recognize molecules present on pathogenic organisms but which show limited interaction with host components. These receptors, referred to as pattern recognition receptors (PRRs), function to promote an innate immune response and include such members as the mannose receptor (MR), scavenger receptors, and Toll-like receptors (TLRs), among others. PRRs bind to conserved microbial structures called pathogen-associated molecular patterns (PAMPs). The expression of these receptors allows the immune system to recognize a wide variety of pathogens that express one or more of these PAMPs, and their engagement initiates the subsequent immune response. Not surprisingly, the PRRs are expressed on cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and natural killer (NK) cells. 1 Binding of microbial products by PRRs elicits a signaling response within the leukocyte, resulting in the production of specific immune modulators. Which PRRs are engaged and in what combination, along with the specific ligands involved, will dictate the overall response by the immune cell. This complexity allows the immune system to tailor its response to a specific pathogen, yet remain flexible enough to recognize a large number of potential pathogens.One of the most...

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

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