Unique origin of exosomes from the Nuclear envelope of migrating neutrophils

Work done in the lab of Dr. Carole Parent at the University of Michigan

About author

Subhash Arya, hailing from Kanpur, Uttar Pradesh, obtained his bachelor’s degree from CSJM University in his hometown. He then moved to New Delhi to pursue his Master’s degree at the School of Biotechnology, Jawaharlal Nehru University. This is where the exposure to an excellent research platform and inspiring faculty nudged him to pursue research as a career. Trying to understand the role of small GTPases in the regulatory mechanisms of endo-lysosomal trafficking, he earned his Ph.D. degree in 2018 under the able guidance of Dr. Amit Tuli at CSIR-IMTech, Chandigarh, India. Later, he moved to the USA, where he is currently working with the Carole Parent group at the University of Michigan, Ann Arbor, to understand the intricacies of neutrophil chemotaxis and other neutrophil functions.

Interview

How would you explain your research outcomes to the non-scientific community?

An army of immune cells in our body remains on the lookout for intruders such as bacteria, and viruses. Of all the immune cells in the blood, neutrophils are the most abundant, first responders, and fastest cell type, capable of migrating as fast as one cell length (1/100th of an mm) per minute. Despite this speed, if they fail to efficiently communicate among themselves, it will be too late by the time they reach the site of injury and prevent/clear bacterial invasion. As soon as we get a cut or burn, the injured tissue releases a feeble amount of damage-associated chemicals to attract nearby neutrophils, but this isn’t enough to stop infection. Therefore, these pioneer neutrophils in turn release a different chemical, leukotriene B4 (LTB4) (a product of fatty acids) which brings more neutrophils from blood to the injured tissue, to efficiently trap and clear out the foreign material and cellular debris. To protect from the hostile extracellular environment, the LTB4, together with the machinery synthesizing this chemical messenger, are packaged in tiny vesicles called exosomes and released outside from the back of migrating neutrophils. Notably, instead of originating from the outer membrane of the cells, the plasma membrane, as happens in most of the cells in the body, the biogenesis of LTB4-containing exosomes originates at the nuclear envelope (NE) of the multilobed nucleus of the neutrophils. The unusual and highly malleable shape of the neutrophil nucleus enables them to squeeze through tight spaces when arriving at the site of injury. The nuclear envelope has regions enriched with waxy lipid molecules called the ceramides, which is where all the LTB4 synthesis machinery congregates. Interestingly, now we know that disruption of these waxy regions inhibits generation of NE-derived LTB4-synthesizing exosomes.

Since neutrophils are necessary to control infection, both the imbalance in neutrophil recruitment cascade and over-exuberant neutrophils can lead to uncontrolled inflammation, thereby aggravating the tissue injury. Understanding precise mechanisms of how neutrophils are summoned open avenues for potential drug targets.

How do these findings contribute to your research area?

Besides providing mechanistic insights into the enigmatic and almost instantaneous arrival of neutrophils at the sites of infection or injury, these findings open the possibility for the existence of a completely different class of exosomes, derived from nuclear envelope, in other cell types.

“Understanding precise mechanisms of how neutrophils are summoned open avenues for potential drug targets.”

What was the exciting moment during your research?

During this project, we were able to visualize the budding and vesiculation of the nuclear envelope along with its molecular mechanism. More so, with nanoscale resolution 4x expansion microscopy, we could observe the presence of intraluminal vesicles (which later are secreted as exosomes) within the NE-derived multivesicular bodies (MVBs). But it was an ‘aha-moment’ as soon as we noticed that NE-derived MVBs and exosomes are distinct from plasma membrane-derived conventional MVBs and exosomes.

What do you hope to do next?

I guess “Hope” is the right word to go with, as, in research, it all depends on the outcome of experiments. But I would love to explore how cancer cells smartly establish their favorable niche in a distant tissue, way before the cancer cell metastasize to that tissue.

Where do you seek scientific inspiration from?

Although not trained with a psychology background, I love learning about the thinking process, the sheer desire, the need, that governs human/animal behavior, their action, and the outcomes. I believe that our world either micro, macro, or celestial, is governed by the same set of rules, all we need is to correlate, imagine and undertake a scientific process to understand what we want to understand, so yes, my inspiration is everyday life and its problems.

How do you intend to help Indian science improve?

So many brilliant Ph.D.(s) leave India every year to pursue research abroad for several well-known reasons (no need to reiterate) and don’t return, mostly because of the lack of opportunities in India, and the scope of making financial and scientific progress outside. In my opinion, this needs to be changed and efforts should be made by both the Indian government and the Indian postdocs outside. To begin with I would love to get back.

Reference

Arya, S.B., Chen, S., Jordan-Javed, F. et al. Ceramide-rich microdomains facilitate nuclear envelope budding for non-conventional exosome formation. Nat Cell Biol 24, 1019–1028 (2022). https://doi.org/10.1038/s41556-022-00934-8

Copy Editor

Anjali Mahilkar

Postdoctoral Fellow at University of Michigan

Anjali is an evolutionary biologist working as a postdoctoral researcher in the department of Ecology and Evolutionary Biology at University of Michigan, Ann Arbor. Her research interests mainly lie in understanding the relationship between natural selection, adaptation and drift in deciding the evolutionary fates of biological functions as well as of whole organisms. She has a PhD from IIT Bombay where her research focused on understanding the process of speciation. Anjali also has her Masters from IIT Kanpur and Bachelor’s from NIT Raipur. She also had short work stints at Dr. Reddy’s Institute of Life Science and at a Central University in Chhattisgarh. She is interested in science communication and volunteers for several organizations towards the same. Although not an avid reader, she likes to read fiction in her free time.

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