Swati Bhattacharyya

Research Statement: Systemic sclerosis (SSc) has high mortality due to fibrosis and microvasculopathy in multiple organs. Vascular injury and evidence of cellular and humoral autoimmunity, including activated T and B cells, dendritic cells, and macrophages, are prominent in SSc, particularly in patients with early-stage disease. However, later stages of SSc are dominated by tissue fibrosis, and inflammatory cell infiltration in target organs is sparse. The pathogenesis of SSc needs to be better understood, and effective treatments are lacking. Understanding how the autoimmune/inflammatory, vascular, and fibrotic processes network in SSc to dictate disease evolution remains a significant challenge in the field. Current thinking suggests a model for pathogenesis whereby exposure of genetically susceptible individuals to certain forms of environmental or toxic injuries elicits inflammation that, together with vascular injury, triggers a cascade leading to fibroblast activation and non-resolving fibrosis.
A unifying fibrosis paradigm is myofibroblast plasticity, by which quiescent mesenchymal cells transform into persistently activated myofibroblasts. Transforming growth factor-beta(TGF-b) is a key mediator of myofibroblast activation and aberrant extracellular matrix (ECM) synthesis in fibrotic diseases. Interactions between early vascular changes and immunological alterations generate the characteristic SSc phenotype. However, the triggers for vascular injury and the nature of interaction with fibrosis remain elusive. One mechanism is an endothelial-to-mesenchymal transition (EndoMT), a cellular transdifferentiation process where endothelial cells (ECs) lose their characteristic morphology and acquire myofibroblast-like features. Recent studies using single-cell technologies show a discrete gene expression pattern associated with vascular injury in SSc skin biopsies and changes suggestive of endoMT. Loss of dermal white adipose tissue (dWAT) is a major histopathological feature of SSc. Our results and several recent publications indicate that resident adipocytes in the dermis are lost in human and mouse skin at an early stage of fibrosis. Yet, the underlying mechanisms and their contribution to fibrosis are unknown. Transcriptome analysis demonstrated the downregulation of adipogenesis-associated genes in SSc skin biopsies. Further, a randomized clinical trial with a novel Wnt inhibitor in SSc showed up-regulated adipogenesis gene signatures in the skin following treatment. I hypothesize that SSc skin fibrosis partially results from myofibroblast differentiation of mesenchymal progenitor cells at the expense of their adipogenic differentiation, disrupting the homeostatic balance. While the published data indicate that resident skin adipocytes are lost in SSc and mouse fibrosis concomitant with ECM expansion, the significance and the mechanisms/factors that drive AMT in tissue fibrosis are unknown. Understanding the regulation of AMT and endoMT in the pre-fibrotic stage of SSc could offer clues to early pathogenetic events and new therapeutic targets for SSc.Genome-wide association studies in SSc have uncovered multiple single-nucleotide polymorphisms (SNP) at the TNFAIP3 locus, encoding the ubiquitin-editing enzyme A20, which is strongly linked with disease susceptibility and fibrotic manifestations across multiple ethnic cohorts. How these genetic variants are associated with altered A20 expression or function potentially and in which cell types (immune versus non-immune) represent major unanswered questions. TNFAIP3 encodes the pleiotropic ubiquitin-editing enzyme A20, which is linked to various chronic autoimmune and inflammatory conditions. A pivotal role of A20 is the suppression of NF-κB signaling to limit the intensity and duration of inflammatory responses in immune cells. The absence of A20 in mice phenocopies multiple autoimmune and inflammatory conditions, while A20 loss-of-function mutations are associated with severe immune and inflammatory diseases in humans. While the expression, regulation, and mechanism of action of A20 have been extensively characterized in the context of inflammatory and autoimmune diseases linked to TNFAIP3 variants, little is currently known regarding A20 in the context of SSc, including its regulation and function in tissue-resident stromal cells and its potential pathogenic role in organ fibrosis. I showed that mice with global loss-of-function of A20 in all tissue, or restricted to fibroblasts, demonstrated exaggerated inflammatory and fibrotic responses in the skin and lung. Thus, we uncover a novel cell-intrinsic role for A20 in the negative regulation of profibrotic fibroblast responses. These results suggest a novel and distinct fibroblast cell type-specific role for A20 in modulating fibrosis. However, the role and mechanism of A20 in regulating the differentiation of adipocytes and endothelial cells into pathogenic myofibroblasts in dWAT atrophy and microvasculopathy characteristic of SSc have not been investigated. Our preliminary results indicate that A20 abrogated TGF-β-induced EndoMT. Moreover, A20 decreased AMT while enhancing adipogenesis in adipocyte-derived stem cells (ADSC). Based on our results, we hypothesize that A20 restrains fibrosis propensity via a previously unrecognized function by negatively regulating adipocyte-mesenchymal differentiation (AMT) and endoMT, and compromised A20 function in SSc underlies sustained fibrosis, the hallmark of the disease. A20 expression is regulated by its DNA-binding repressor DREAM, which, by entering the nucleus, binds to the A20 promoter to repress its transcription. The regulation of DREAM is poorly understood and has never been examined in the context of SSc or fibrosis. We hypothesize that boosting A20 by blocking DREAM nuclear localization will restrain fibrotic myofibroblast transitions, thereby slowing fibrosis progression or promoting resolution, representing an innovative potential treatment strategy for SSc.

Research Interests

• Role of innate immune signaling, its negative regulators, their implications in transgenic mice, and the use of small molecule inhibitors in preclinical models of fibrosis for therapy.
• Role of zinc metabolism in organ fibrosis and targeted therapy
• The role of epigenetics in fibrosis
• Predict pathway-specific baseline biomarkers to identify a subset of scleroderma patients for personalized therapy. Current FDA guidelines recommend pairing the approval of new therapeutics with baseline biomarkers to predict which responders are most likely to benefit from treatment.

Besides, I was involved in numerous patient-oriented translational research projects in collaboration with our clinical investigators at Northwestern University and the University of Michigan. My research is directly relevant to clinical applications that improve patient outcomes.

Clinical Interests

Using Scleroderma patients’ skin biopsies, skin fibroblasts, scleroderma skin keratinocytes, healthy skin fibroblasts, and keratinocytes to implicate my in vitro and preclinical studies in disease or disease models