Laboratory of Alexander G. Marneros, MD, PhD

Overview

Our laboratory studies the cellular and molecular circuits that control epithelial differentiation, inflammation, and regeneration in health and disease, with a particular emphasis on aging diseases. Our research reveals new disease mechanisms and therapeutic targets with relevance far beyond the skin, including for renal fibrosis and age-related macular degeneration.

Research Projects

Our laboratory investigates how disrupted epithelial differentiation, inflammation, and wound-repair responses drive genetic skin disease and age-related disorders. We combine human genetics, mouse models, multi-omics, and functional studies to uncover disease mechanisms and translate those discoveries into new therapeutic strategies. Our work is highly interdisciplinary, disease-focused, and supported by four major NIH-funded research programs. Although rooted in dermatology and wound healing, our discoveries have also advanced understanding in kidney disease, fibrosis, macrophage biology, angiogenesis, and neovascular age-related macular degeneration.

From wound healing to epithelial differentiation, developmental signaling, and fibrosis

A central theme of our research is that clinical observations can lead to fundamental biological discovery. Based on patient encounters, our studies of aplasia cutis congenita (ACC), a congenital scalp defect, uncovered the first genetic causes of this disorder and transformed our understanding of how epithelial tissues develop and are maintained. We identified pathogenic mutations in BMS1 and KCTD1 in patients with aplasia cutis congenita, then used these discoveries to define molecular pathways that regulate epithelial differentiation in both skin and kidney. Our work revealed a critical AP-2β/KCTD1 axis required for distal convoluted tubule differentiation and maintenance, and showed that loss of this pathway causes inflammation, fibrosis, and renal dysfunction. This work identified novel therapeutic targets for preventing progressive renal fibrosis.
We also discovered that ACC is not caused by a primary keratinocyte defect but instead arises from abnormal cranial neural crest–derived mesenchyme that fails to support formation of the overlying epidermis. This revealed a new mesenchymal-to-epithelial inductive signaling mechanism in scalp development. Together, these studies show how rare disease genetics can uncover broadly important principles of development, tissue homeostasis, and fibrosis.

Keratinocyte–immune cell interactions in cutaneous inflammation

Skin inflammation is shaped not only by immune cells, but also by intrinsic abnormalities in keratinocytes. We study the earliest pathogenic events that initiate inflammatory skin disease, with the goal of identifying interventions that can block inflammation before it becomes chronic. Our work showed that impaired keratinocyte differentiation can be an initiating event in cutaneous inflammation. In particular, we identified the transcription factor AP-2α as a key regulator of the transition from keratinocyte proliferation to terminal differentiation. Loss of AP-2α drives keratinocyte hyperproliferation, defective differentiation, and inflammatory changes that resemble psoriasis. We further discovered that AP-2 activity is controlled by KCTD1/KCTD15 complexes, linking epithelial differentiation to inflammatory disease and skin appendage development. These findings highlight keratinocytes as active drivers of inflammation and suggest new therapeutic strategies aimed at restoring epithelial homeostasis.

Macrophage polarization and inflammatory angiogenesis

Our work on wound healing led us to investigate inflammatory angiogenesis, a process that contributes to chronic wounds, neovascular age-related macular degeneration (AMD), and tumor progression. We found that proangiogenic macrophage polarization is a major driver of pathologic neovascularization and that blocking these macrophage states can suppress disease. Using global quantitative proteomics, phosphoproteomics, and transcriptomics, we mapped the signaling networks that control macrophage polarization and identified actionable therapeutic targets. These studies showed, for example, that MEK signaling regulates PPARγ/retinoic acid pathways required for IL-4-induced proangiogenic macrophage polarization, and that MEK inhibition can block this program in vitro and in vivo. Our goal is to translate these mechanistic insights into new therapies for angiogenesis-driven disease.

Inflammasomes and neovascular age-related macular degeneration (AMD)

We study the inflammatory mechanisms that drive neovascular AMD, one of the most common causes of blindness, as it represents a disease caused by a maladaptive, chronic wound-healing response in the retina. To overcome a major barrier in the field, we identified the first genetic mouse model that spontaneously forms choroidal neovascularization without experimental injury. Using this model, we demonstrated that proangiogenic macrophages are key mediators of disease and discovered that inflammasome activation promotes choroidal neovascularization through IL-1β signaling. Our work further showed that both NLRP3-dependent and NLRP3-independent inflammasome pathways contribute to disease progression, supporting inflammasome inhibition as a promising therapeutic strategy. More recently, we found additional factors produced by the retinal pigment epithelium that promote neovascular age-related macular degeneration independently of VEGF-A, providing promising new therapeutic opportunities.

Jackelyn Raymundo

Christina Eng

Bill Senapati

Poula Fahmy

Brianna Lee

Molly Rynne

Publications

View publications

Selected Publications

1. Raymundo JR, Makkar J, Fasci M, Driskell R, Marneros AG. TGFα is required for hair follicle function during aging and its loss leads to progressive alopecia. J Invest Dermatol., 2025, S0022-202X(25)03601-2.
2. Senapati B, Raymundo J, Makkar J, Driskell R, Marneros AG. KCTD1/KCTD15-mediated repression of AP-2α/AP-2β is required for proper skin appendage development and epidermal homeostasis. J Invest Dermatol., 2025, S0022-202X(25)02832-5.
3. Zhang H, Raymundo JR, Daly KE, Zhu, W, Senapati B, Zhong H, Ahilan AR, Marneros AG. AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis. J Invest Dermatol., 2024; doi: 10.1016/j.jid.2023.12.017.
4. Raymundo JR, Zhang H, Smaldone G, Zhu W, Daly, KE, Glennon BJ, Pecoraro G, Salvatore M, Devine WA, Lo C, Vitagliano L, Marneros AG. KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis. J Clin Invest., 2023; e174138. doi: 10.1172/JCI174138.
5. Lamontagne JO, Zhang H, Zeid AM, Strittmatter K, Rocha AS, Williams T, Zhang S, Marneros AG. Transcription factors AP-2α and AP-2β regulate distinct segments of the distal nephron in the mammalian kidney. Nature Communications, 2022; 13(1): 2226. doi:10.1038/s41467-022-29644-3.
6. Zeid AM, Lamontagne JO, Zhang H, Marneros AG. Epidermal growth factor deficiency predisposes to renal disease. FASEB J, 2022; e22286; doi:10.1096/fj.202101837R.
7. He L, Jhong JH, Chen Q, Huang KY, Strittmatter K, Kreuzer J, DeRan M, Wu X, Lee T, Slavov N, Haas W, Marneros AG. Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors. Cell Reports, 2021;37(5):109955. doi:10.1016/j.celrep.2021.109955.
8. Marneros AG. Magnesium and calcium homeostasis depend on KCTD1 function in the distal nephron. Cell Reports, 2021, 10.108616.
9. Malsy J, Alvarado AC, Lamontagne JO, Strittmatter K, Marneros AG. Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization. eLife, 2020; 9:e60194. doi: 10.7554/eLife.60194.
10. Marneros AG. AP-2β/KCTD1 control distal nephron differentiation and protect against renal fibrosis. Dev Cell, 2020, 54(3):348-365.e5 PMID: 32553120.
11. Marneros AG. Effects of chronically increased VEGF-A on the aging heart. FASEB J, 2018, 32(3):1550-1565.
12. Strittmatter K, Pomeroy H, Marneros AG. Targeting PDGFRβ+ scaffold formation inhibits choroidal neovascularization. Am J Pathol, 2016, 186(7): 1890-1899. **(Cover article)**.
13. Marneros AG. Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms. EMBO Mol Med, 2016, 8(3): 208-231. PMID: 26912740
14. He L, Marneros AG. Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization. J Biol Chem., 2014, 289(12):8019-8028.** (Cover article)**.
15. Ablonczy Z, Dahrouj M, Marneros AG. Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. FASEB J., 2014, 28(5):2369-2379.
16. Marneros AG. NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration. Cell Reports, 2013, 4(5): 945-958. **(Cover article)**.
17. Marneros AG*, Beck AE*, Turner EH*, McMillin MJ, Edwards MJ, Field M, de Macena Sobreira NL, Perez AB, Fortes JA, Lampe AK, Giovannucci Uzielli ML, Gordon CT, Plessis G, Le Merrer M, Amiel J, Reichenberger E,
18. Shively KM, Cerrato F, Labow BI, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ; University of Washington Center for Mendelian Genomics. Mutations in KCTD1 cause Scalp-Ear-Nipple Syndrome. Am J Genet, 2013, 92(4):621-626. *co-first author.
19. Marneros AG. BMS1 is mutated in aplasia cutis congenita. PLoS Genet, 2013, 9(6):e1003573. **(F1000: Selected as "Must Read" by The Faculty of 1000)**.

Open Positions:

A Postdoctoral Research Fellow position and a Research Technician position are available. Interested candidates should send their information including CV and the name of 2-3 references to Dr. Alexander G. Marneros: amarneros@mgh.harvard.edu