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What is phagocytosis?

A process where the immune cells that work as the first line of defence, often eat up pathogens or dead cell debris (also referred to as 鈥淐argo鈥� in this article), is known as phagocytosis.

An Insight into Professor Ganguly鈥檚 Research:

In regards with his research, Professor Ganguly shares how it was observed in the case of one such immune cell (known as plasmacytoid dendritic cells or PDCs) that the physical nature of dead cell debris or cargo (especially size) it gobbles in often leads to different functional outcomes. It was particularly evident in the case of phagocytosis of DNA molecules. Professor Ganguly鈥檚 lab within the Datla Human Immunome Lab, in the Trivedi School of Biosciences, has been working on these particular immune cells.

However, how cargo size sensing occurs remains unclear, opening avenues for further research.
An explanation for this would greatly help in understanding the function of these cells, not only in immune responses against infections but also in diseases in which these cells are turned against the host, leading to autoimmunity.

The Approach:

Professor Ganguly and his team utilised DNA molecules with an inherent property of forming cargoes of different sizes during phagocytosis by PDC and explored whether the phagocytic mechanism itself differed with cargo size. And, they found that this was not the case.

Continuing the research, the team investigated whether greater cell membrane buckling, which results in local membrane tension, was related to it.

What experiments were carried out

In collaboration with Prof. Bidisha Sinha at the Indian Institute of Science Education and Research, Kolkata, the team utilised a microscopic technique called interference reflection microscopy or IRM, to measure the tension on the cell membrane around the cargo-entry point on the cell surface. They found indeed that the local membrane tension was increased in response to a larger DNA cargo. Then the question was whether and how this was linked to the functional changes that the cell was experiencing. They found, by confocal microscopy, that the mechanosensor ion channel Piezo1 formed distinct clusters on the cell surface in response to larger cargoes. It was also found that when the abundance of these ion channels was reduced, the functional outcome associated with larger cargoes changed.

Results:

Experimental findings in the lab indicated that higher membrane tension was generated locally on the plasma membrane in response to bigger cargo. This led to activation of the ion channel Piezo1.

Piezo1 is a cell membrane-resident mechanosensor protein and can sense membrane stretch and respond by letting calcium ions into the cells.

This calcium influx during phagocytosis in turn regulated intracellular trafficking and different functional outcomes (i.e., the types of soluble mediators of the immune response, also known as cytokines, released).

Potential Impact:

Talking about the potential benefits of the study, Professor Ganguly says, 鈥淭he insights gathered from this study are important in different contexts of immune response, whether it is protective immunity against infectious agents or autoimmune diseases.鈥� He also underlines that these mechanosensory ion channels, i.e. Piezo1, may also be potentially targeted for therapeutic goals in different clinical contexts.

Conclusion:

In summary, Professor Dipyaman Ganguly and the team at Datla Human Immunome Lab explored the innate immune system by which plasmacytoid dendritic cells or PDCs, have different functional outcomes due to the physical nature of the cargo (especially size) that they gobble. In this process, they come across Piezo1, a mechanosensory protein which impacts downstream processes during cargo uptake to regulate innate immune signalling and can thus act as a possible therapeutic target.

Edited by Priyanka and Simran Wadan for the Research and Development Office.

This blog has been adapted from the original article, available .