Alexander Marneros

Alexander Marneros

Associate Professor of Dermatology
Alexander Marneros
My laboratory studies pathomechanisms in wound healing and inflammation, utilizing human genetics, mouse genetics, and innovative OMICs technologies, as well as a broad array of functional assays. Our investigations are highly interdisciplinary and have resulted in three major NIH-funded research programs that all originated from our work on wound healing/inflammation and have led to discoveries in other areas of Medicine as well. All our projects are disease-oriented and have strong translational relevance.
Research Program I: From wound healing to macrophage polarization mechanisms and angiogenesis.
Our work on wound healing led us to study inflammatory angiogenesis, which exacerbates not only wound healing disorders but also neovascular age-related macular degeneration (AMD) and tumor growth. We found in animal models of wound healing and neovascular AMD that polarization of macrophages to a proangiogenic subtype strongly promotes inflammatory angiogenesis, which can be blocked by ablation of these macrophages (Cell Reports, 2013; Am J Pathol, 2013; J Biol Chem, 2014). Identifying drugs that prevent this polarization process represents an important unmet clinical need. Global quantitative time-course proteomics, phosphoproteomics, and transcriptomics at unprecedented temporal resolution and scale allowed us to identify specific signaling nodes that are required for macrophage polarization. Drug screens identified drugs that selectively inhibited IL-4-induced proangiogenic macrophage polarization by blocking some of these signaling nodes. For example, we discovered that MEK controls PPARg/retinoic acid signaling to induce IL-4-induced macrophage polarization, which was blocked by MEK inhibitors both in vitro and in mouse models of wound healing and neovascular AMD (Cell Reports, 2021). Our results offer exciting novel therapeutic opportunities to improve diseases that are promoted by these proangiogenic macrophages, some of which are already being tested in clinical trials in patients with neovascular AMD.
Research Program II: From wound healing to inflammasomes and neovascular AMD.
We investigate pathomechanisms that drive neovascular AMD, as this disease is promoted by inflammation that resembles a prolonged wound healing reaction and leads to choroidal neovascularization (CNV). Progress in this field has been limited by a lack of a mouse model that forms spontaneous CNV. We identified the first genetic mouse model of neovascular AMD, Vegfahyper mice, that consistently develops progressive CNV lesions without experimental injury due to increased VEGF-A and which extend into the subretinal space as in the human disease (Cell Reports, 2013, FASEB J, 2014). This neovascular AMD mouse model confirmed the critical role of proangiogenic macrophages in CNV formation. Moreover, we also discovered that increased NLRP3 inflammasome activation promotes CNV via secretion of IL-1b, whereas genetic or pharmacologic targeting of inflammasomes potently inhibits CNV (EMBO Mol Med, 2016). Our recent new data answer key unresolved questions in the AMD field and show that not only NLRP3-dependent but also NLRP3-independent inflammasome activation in macrophages and microglia, but not in RPE cells, promotes CNV (eLife, 2020). These findings have important clinical relevance and suggest that inflammasome inhibitors can improve current neovascular AMD therapies.
Research Program III: From wound healing to the identification of novel regulators of epithelial differentiation and fibrosis.
We use human genetics to identify critical regulators of skin formation and wound healing by discovering the gene mutations that cause aplasia cutis, which manifests with skin defects and wounds at birth. We identified the first gene for aplasia cutis as the ribosomal GTPase BMS1 that, when mutated, leads to a ribosome biogenesis defect (PLoS Genetics, 2013). We also discovered causative gene mutations in KCTD1 in patients with Scalp-Ear-Nipple (SEN) syndrome who have aplasia cutis and additional abnormalities (Am J Hum Genet, 2013). We generated mice that lack KCTD1 and found, unexpectedly, that KCTD1 is a critical regulator of distal nephron differentiation (Dev Cell, 2020). Moreover, we found that KCTD1 is a key regulator of magnesium and calcium transport processes in the distal nephron of the adult kidney (Cell Reports, 2021). We also found that the two closely related transcription factors AP-2a and AP-2b have distinct spatiotemporal roles in separate segments of the distal nephron, where they regulate the function and development of these segments (Nature Communications, 2022). The findings in the kidney guided us to uncover critical roles of AP-2a/AP-2b and KCTD1 also for skin and hair follicle formation.

Contact Information

Cutaneous Biology Research Center
Massachusetts General Hospital
CNY-149, RM 3.216
Charlestown, MA 02129