Controlling inflammatory immune response in Macrophages

Controlling inflammatory immune response in Macrophages

Controlling inflammatory immune response in Macrophages

Dr Soumen Basak, Intermediate Fellow

National Institute of Immunology (NII), New Delhi  

A select set of dedicated intra-cellular signaling pathways determine the inflammatory response of the host to invading pathogens.  These pathways are ubiquitous in nature, and yet various cell types give rise to strikingly different responses.  To understand the mechanism underlying this cell type-specific control, we focused on the NF-kB signaling system, which plays a key role in the inflammatory immune response, and transduces signals through the canonical as well as the noncanonical pathways.

In a collaborative study, we found that in fibroblasts and epithelial cells the NF-kB system integrates canonical and noncanonical signals to induce a sustained inflammatory response, which helps eliminating the invading pathogens. We also found that the NF-kB pathway crosstalk operated differently in white blood cells or macrophages.  Interestingly, the NF-kB network was identical and the regulatory biochemical mechanisms were preserved between macrophages and fibroblasts.  Combining biochemistry and mathematical modeling, we instead identified quantitative differences in the biochemical rate parameters associated with the NF-kB pathway between macrophages and fibroblasts.  Remarkably, these quantitative differences were sufficient for insulating the canonical NF-kB pathway from noncanonical signals that ensured rather transient inflammatory NF-kB response in macrophages.  We propose that this pathway-insulation limits the deleterious effects of macrophage-mediated inflammation. 

Our study illustrates that despite the presence of identical signaling networks in cells of diverse lineages, emergent crosstalk between signaling pathways is subject to cell type–specific regulation.

Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages. Chatterjee B, Banoth B, Mukherjee T, Taye N, Vijayaragavan B, Chattopadhyay S, Gomes J, Basak S. Science Signaling. Dec 6, 2016


Image Credit University of Edinburgh, Wellcome Images 
Macrophage with phagocytic vesicle and lysosomes

Description: Macrophage from a human tonsil containing a phagocytic vesicle (pink) and lysosomes (dark red). The lysosomes degrade the ingested material by subjecting it to strong chemical and enzymatic attack.
Transmission electron micrograph 1980 - 2000