Quarter in Review: Basic Science

Upendra Rathore MBBS, MD, DNB, DM (Clinical Immunology and Rheumatology)
Assistant Professor, Department of Clinical Immunology and Rheumatology, SGPGI, Lucknow

Study in focus 1: Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9

Study Synopsis
Fibroblasts are the major players involved in organ fibrosis owing to a chronic disease stimulus. The exact role of endothelial cells in driving fibrosis is unclear. The authors in this study have tried to demonstrate whether Sox9 overexpression in endothelial cells triggers fibrosis and its ablation mitigates it.
Sox9 is a transcription factor involved in homeostasis and is essential for embryogenesis and chondrogenesis. In the present study, authors have used fibrosis mouse models (systolic heart failure induced by pressure overload: transcatheter aortic constriction, diastolic heart failure induced by high-fat diet and nitric oxide synthase inhibition, pulmonary fibrosis induced by bleomycin and liver fibrosis by choline-deficient diet) to demonstrate overexpression of Sox9 in endothelial cells leads to organ fibrosis in addition to increase in the upregulation of profibrotic genes.

Deletion of Sox9 resulted in the prevention of organ fibrosis and decreased fibrosis in an already established disease model. Bulk and single-cell RNA sequencing of mouse endothelial cells revealed that Sox9 leads to induction of proinflammatory & pro fibrotic genes which in turn propagates extracellular matrix and fibrosis.

This study also highlights that the endothelial cells undergo differentiation to endothelial mesenchymal activation but not complete transition to Endo MT.
In the future, strategies that enable Sox9 downregulation in ECs might develop to mitigate or prevent fibrosis.

Study in focus 2: Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne

Study Synopsis
PAPA (Pyogenic Arthritis with Pyoderma Gangrenosum and Acne) is an autoinflammatory disorder characterized by mutation in the PSTPIP1 gene. The pathophysiology of PAPA syndrome is poorly understood and prior mouse model studies have failed to recapitulate the human PAPA syndrome. In this study, the authors have tried to delineate its pathogenetic pathway with emphasis on IFNγ involved in a feedback loop driving the diseases and exploring the possibility of interrupting this amplification loop by targeting the JAK-STAT pathway.

The authors have demonstrated in the human myeloid cell line model that PSTPIP1 mutations activate the pyrin inflammasome through a non-canonical mechanism and not by the classical NLRP3, NLRC4, or AIM2 inflammasome pathway with pyrin phosphorylation. PAPA-associated PSTPIP1 mutations (A230T, E250Q) activate the pyrin inflammasome.

This non-canonical pyrin activation leads to the induction of positive feedback through the release of IL-1b and IL18 that drives IFNγ in the skin of PAPA patients, leading to further induction of pyrin expression. In addition in ex vivo experiments, JAK inhibitor blocked this vicious cycle of IFN-y-mediated pyrin activation and IL18 and IL-1b release leading to clinical improvement in all the five patients involved in the study.

This study introduces the concept of various other pathogenetic pathways in PAPA syndrome in addition to pyrin inflammasome activation through pyrin phosphorylation. It also gives an insight into the use of JAK inhibitors in these disorders in addition to the IL 1 inhibitors. 


  1. Manavski Y, Lucas T, Glaser SF, Dorsheimer L, Günther S, Braun T, et al. Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization. Circ Res. 2018 Mar 2;122(5):670–7.
  2. Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, et al. Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. Curr Genomics. 2010 Nov;11(7):519–27.