It was all about macrophages for ARVO 2024 Day Four’s slate of award lectures. Famed researchers Drs. Martine Jager and Daniel Saban were recognized for their work on the complex—and unexpected—roles of these cells in ocular biology.
Macrophages were in the air on Day Four of the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024), as these hungry immune cells took center stage at both of the day’s award lectures—the Mildred Weisenfeld Award for Excellence in Ophthalmology and Cogan Award.
Delivered by former ARVO President Dr. Martine Jager (University of Leiden, Netherlands) and ascendant ocular immunobiologist Dr. Daniel Saban (Duke University, USA), respectively, these lectures explored the mercurial nature of these important cells—and spoke about the possibility of harnessing their power for novel therapeutic applications.
The fascinating duality of macrophages
Dr. Martine Jager, already a titan of vision science and research, can now add the Weisenfeld Award to her well-stocked trophy case of awards for excellence in eye care.
The Award is named after Mildred Weisenfeld, a retinitis pigmentosa sufferer blinded at age 23 and the founder and lifelong head of Fight for Sight. Mrs. Weisenfeld tirelessly campaigned to shift the paradigm in the mid-20th century from simply caring for the blind to funding research on how to stop its root causes.
After paying tribute to Mrs. Weisenfeld and reflecting on her storied journey to the highest honors in ophthalmology, including being the first foreign-born president of ARVO, Dr. Jager took the audience through a whirlwind tour of macrophages and their complex role in ocular biology.
Macrophages, according to Dr. Jager, are marked by their duality in ocular pathologies. On the one hand, she explained, they are a hungry force for good in the immune system in diseases like acanthamoeba keratitis. “They’re like Pacman,” Dr. Jager said. “And what they do is eat danger.”
However, macrophages’ lesser known, darker side is perhaps more important in ocular disease, and this is what Dr. Jager has spent a large part of her career investigating. And what a fruitful career it has been for Dr. Jager and her colleagues researching these monocytes.
Their findings have been many and varied. In glaucoma, the presence of macrophages increases pressure-related damage. They stimulate rejection of corneal transplants, worsen corneal herpetic inflammation, and induce inflammation in age-related macular degeneration.
The story for tumors, however, is more nuanced—and according to Dr. Jager, her work with uveal melanomas could provide avenues for novel therapeutics.
Uveal melanoma tumors with mutated, inactivated BAP1 genes are much likelier to metastasize, Dr. Jager explained. “We came up with this process for uveal melanoma: You have a mutation in BAP1, HIF1a goes up, macrophages stream in, you get inflammation in the tumor, which then leads to blood vessel formation,” she said.
“These are all M2 macrophages, which means immunosuppression, and that subsequently leads to metastasis formation.”
True to the Weisenfeld Award spirit, Dr. Jager then explained how these findings are being translated into action. Aura Biosciences (Boston, USA) is currently working on a therapeutic, called bel-sar, for ocular cancers that combines a photoactivated cytotoxic nanoparticle with immune response.
When investigating this dual treatment modality, Dr. Jager found that it worked unexpectedly well on pigmented tumors in mice, defying conventional wisdom. But she also found something even more surprising involving—you guessed it—macrophages.
“We were also studying the effect of [this treatment] on the immune response, and we found something that we had not expected at all,” she said. “When bel-sar was used on tumors, both pigmented and non-pigmented, the good macrophages increased and the pro-angiogenic ones went down.”
This immune response could be pivotal in bringing down mortality rates in the killer cancers of the eye. And in the end, this is what the lecture’s namesake was all about. “
“As Mildred Weisenfeld already knew, by doing research, we can understand eye disease and treat our patients better than we did before,” said Dr. Jager in conclusion. “Mrs. Weisenfeld found out she was losing sight, and now people are using gene therapy to make progress and help new generations of children grow up seeing.”
Double macrophage delight
Dr. Daniel Saban followed with another foray into the world of macrophages for the Cogan Award Lecture. This Award, named for Dr. David G. Cogan, is given to a promising researcher in vision science under the age of 45. Dr. Saban, who already has a lab of his own at Duke, fits the bill.
Unlike Dr. Jager, however, Dr. Saban focused on the positive side of macrophages—specifically tissue-resident (TR) macrophages, a longer-lived subtype of macrophage waiting in the wings at select points in the body to deliver an immune response.
Specifically, Dr. Saban looked at macrophages in the context of non-immune functions. The researchers in Dr. Saban’s lab have looked at TR macrophages in various contexts—the conventional outflow pathway, the cornea and the outer retina.
“What you see is a theme across all of these settings,” he explained. “There are macrophages right there at the critical barrier tissues to maintain proper function of that tissue.”
Forthcoming work by a member of his lab, Sejiro Littleton, PhD, has shown that TR macrophages congregate in the basement membrane of the cornea near nerves where Schwann cells penetrate to enter the epithelium.
According to Dr. Littleton’s research, these macrophages support the nerves—but not all nerves, according to further research in Dr. Saban’s lab. Mice with depleted macrophages lost their mechanosensitive blink reflex, but maintained sensitivity to heat and cold. This suggests an interaction where the macrophages are co-opting Schwann cells to help selectively maintain corneal mechanosensory cells.
In glaucoma, Dr. Katy Liu’s lab (Duke University, USA), working in tandem with Dr. Saban’s found that TR macrophages hang out mostly in the trabecular meshwork, but not in Schlemm’s canal or distal vessels.
However, when Dr. Liu depleted the TR macrophages, the functioning of the primary outflow pathway suffered. The working hypothesis is that these macrophages congregate in the trabecular meshwork near the Schlemm’s canal at the blood-aqueous barrier to enable Schlemm’s canal to support primary outflow.
Lastly, Dr. Saban touched on the outer retina and the retinal pigment epithelium (RPE). In this context, the resident microglia have a protective effect on the RPE. “This was quite a shock to us,” said Dr. Saban. “Microglia are moving to the sublevel space, attaching to the apical side of the RPE and actually rendering protection, rather than what we previously thought to be a more damage-type response.”
“We found that microglia have unique access to the subretinal space,” he summarized. “And they are seemingly not contributing to inflammation. They’re able to clear debris and support the tissue in the relative absence of inflammation.”
It is this last observation that Dr. Saban is now pursuing, with his startup Piximune Therapeutics (North Carolina, USA) a new class of therapeutics. He ended his talk by discussing the therapeutic potential of macrophages in the retina.
“We are now able to develop a novel class of molecules that can actually switch on an offensive protective pathway,” he said. “We have a tool molecule that we’ve already published in mice, and it is quite protective in this context.”
Fitting, then that Dr. Saban calls TR macrophages the ‘unseen guardians of ocular health’. And just like with Dr. Jager’s research, the world hopes that these unseen guardians can be put to even more work soon to preserve human life and vision.
Editor’s Note: The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2024) is being held from 5-9 May in Seattle, Washington, USA. Reporting for this story took place during the event.
