Ana Codo: When Environmental Particles Disrupt a Fundamental Immune Function

Ana Codo, PhD candidate in Immunology and Microbial Pathogenesis at Weill Cornell Medical College, shared Justin Perry‘s post on LinkedIn, adding:

“I’m thrilled to share that the first paper from my PhD is out today in Immunity by Cell Press!

Here, we investigated how phagocytes, such as macrophages, handle microplastics (MPs) during their normal functions.

One of their essential functions is the phagocytosis of apoptotic cells (ACs), termed efferocytosis, which occurs more than 3 million times per second! You can imagine why this matters.

Previous studies have shown that your body’s macrophages can eat MPs. However, if and how these MPs affect efferocytosis is unknown.

Here, we report the alarming finding that exposure to MPs significantly impairs efferocytosis in multiple mouse tissues and by human macrophages.

Specifically, we found that both mouse and human macrophages exposed to MPs internalize fewer dead cells and have significantly delayed digestion of engulfed dead cells in vitro.

Using multiple mouse models, we found MP exposure disrupted efferocytosis in the lung, liver, and testis in vivo, negatively affecting each tissue. In the case of the testes, this caused decreased fertility in male mice.

Scarily, these effects were not limited to efferocytosis, as MPs also suppressed bacterial, fungal, and antibody-mediated phagocytosis in vitro as well as the phagocytic uptake and killing of A. fumigatus (a fungal infection model) in the lungs of mice in vivo.

We moved beyond phenomenological studies of the effects of MP exposure on cells by mechanistically linking the effects of PS-MP accumulation on efferocytosis to specific changes in metabolic processes required for appropriate AC internalization and degradation.

Our data on MP’s effects on human health raise important biological and epidemiological questions, further supporting the notion that rigorous studies of the cellular and physiological consequences of these environmental pollutants are needed.

I’m deeply grateful to my mentor, Dr. Justin Perry, and my labmates (highlighting here Jesús Romero Pichardo and Shasha Wang) for their incredible support in the lab and during this project’s execution.

Also, a special thank you to all our collaborators who made this project possible.

And I’m thankful for the support that allowed us to pursue this important but understudied (and underfunded) area, especially The National Institutes of Health, Howard Hughes Medical Institute (HHMI), American Heart Association, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine.”

Justin Perry, Associate Member at Memorial Sloan Kettering Cancer Center, shared a post on LinkedIn about a recent article he and his colleagues co-authored, adding:

“Those who know me, know I’m not someone who changes his preferences and behaviors lightly.

As Ron Swanson said, ‘I regret nothing. The end.’ Well, let me tell you about our new study, out from our lab at Memorial Sloan Kettering Cancer Center in Immunity by Cell Press which is the exception.

This is the first paper from our lab under the new The National Institutes of Health/ U.S. Department of Health and Human Services (HHS) guidelines for open access.

Plastics are a ubiquitous part of everyday life, but growing evidence suggests that the microparticles from plastic degradation, microplastics (MPs), pose a significant threat to human health.

These MPs, commonly ingested or inhaled via environmental exposure, first encounter professional phagocytes, such as macrophages (the body’s ‘big eaters’), that live in all tissues of the body and perform essential tasks.

One of these essential tasks, the phagocytosis of dead cells (we call it ‘efferocytosis’), is the process by which our phagocytes literally engulf your body’s dead cells, something that happens more than 3 million times per second! You can see why this matters.

Previous studies have shown that your body’s macrophages can eat MPs. However, if and how these MPs affect efferocytosis is unknown.

Here, we report the alarming finding that exposure to MPs significantly impairs efferocytosis in multiple mice tissues and by human macrophages.

Specifically, we found that both mouse and human macrophages exposed to MPs internalize fewer dead cells and have significantly delayed digestion of engulfed dead cells in vitro.

Using multiple mouse models, we found MP exposure disrupts efferocytosis in the lung, liver and testis in vivo, negatively affecting each tissue. In the case of the testes, this caused decreased fertility in male mice.

Scarily, these effects were not limited to efferocytosis, as MPs also suppressed bacterial, fungal and antibody-mediated phagocytosis in vitro and the phagocytic uptake and killing of A. fumigatus (a fungal infection model) in the lungs of mice in vivo.

We sought to learn how MPs are causing these defects.

The results were striking: The presence of MPs in macrophages engulfing dead cells accumulated the metabolite methylglyoxal (MGO). MGO forms Advanced Glycation End Products, associated with many chronic diseases.

Strikingly, we found increased ‘MGOylation’ (MGO binding) of proteins, including the enzyme G6PD. G6PD is required for efficient degradation of engulfed dead cells.

We next had the crazy idea that, maybe, we could give macrophages the ability to combat MGO accumulation by a process my colleague Kayvan R. Keshari coined ‘metabolic engineering’.

It turns out, there is an enzyme (called Glo1) that detoxifies MGO.

Excitingly, engineering macrophages with Glo1 significantly rescued MP-mediated efferocytosis impairments both in vitro and in vivo!”

Title: Polystyrene microplastic-induced pathophysiology is driven by disruption of efferocytosis

Authors: Ana C. Codo, Jesus E. Romero-Pichardo, Zhaoquan Wang, Mariano A. Aufiero, Tomi Lazarov, Waleska Saitz Rojas, Nicole S. Walker, Achuth Nair, Roger F. Cole, Savannah Adkins, Edward Dong, Kelvin Fadojutimi, Celia Martínez de la Torre, Yael David, Tobias M. Hohl, Frederic Geissmann, Kayvan R. Keshari, Christopher D. Lucas, Justin S.A. Perry

Read the Full Article on Immunity

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