@article {6687, title = {Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis.}, journal = {J Invest Dermatol}, volume = {143}, year = {2023}, month = {2023 May}, pages = {699-710.e10}, abstract = {

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

}, keywords = {Animals, Disease Models, Animal, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Humans, Mice, Mice, Transgenic, Neoplasm Proteins, Scleroderma, Systemic, Skin}, issn = {1523-1747}, doi = {10.1016/j.jid.2022.10.011}, author = {Rana, Isha and Kataria, Sunny and Tan, Tuan Lin and Hajam, Edries Yousaf and Kashyap, Deepak Kumar and Saha, Dyuti and Ajnabi, Johan and Paul, Sayan and Jayappa, Shashank and Ananthan, Akhil S H P and Kumar, Pankaj and Zaarour, Rania F and Haarshaadri, J and Kansagara, Gaurav and Rizvi, Abrar and Zirmire, Ravindra K and Badarinath, Krithika and Khedkar, Sneha Uday and Chandra, Yogesh and Samuel, Rekha and George, Renu and Danda, Debashish and Jacob, Paul Mazhuvanchary and Dey, Rakesh and Dhandapany, Perundurai S and He, You-Wen and Varga, John and Varghese, Shyni and Jamora, Colin} } @article {6688, title = {The expanding impact of T-regs in the skin.}, journal = {Front Immunol}, volume = {13}, year = {2022}, month = {2022}, pages = {983700}, abstract = {

As the interface between the body and the environment, the skin functions as the physical barrier against external pathogens and toxic agents. In addition, the skin is an immunologically active organ with a plethora of resident adaptive and innate immune cells, as well as effector molecules that provide another layer of protection in the form of an immune barrier. A major subpopulation of these immune cells are the Foxp3 expressing CD4 T cells or regulatory T cells (T-regs). The canonical function of T-regs is to keep other immune cells in check during homeostasis or to dissipate a robust inflammatory response following pathogen clearance or wound healing. Interestingly, recent data has uncovered unconventional roles that vary between different tissues and we will highlight the emerging non-lymphoid functions of cutaneous T-regs. In light of the novel functions of other immune cells that are routinely being discovered in the skin, their regulation by T-regs implies that T-regs have executive control over a broad swath of biological activities in both homeostasis and disease. The blossoming list of non-inflammatory functions, whether direct or indirect, suggests that the role of T-regs in a regenerative organ such as the skin will be a field ripe for discovery for decades to come.

}, keywords = {Forkhead Transcription Factors, Homeostasis, Skin, T-Lymphocytes, Regulatory}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.983700}, author = {Hajam, Edries Yousaf and Panikulam, Patricia and Chu, Chung-Ching and Jayaprakash, Haarshadri and Majumdar, Amitabha and Jamora, Colin} } @article {1152, title = {PAI1 mediates fibroblast-mast cell interactions in skin fibrosis.}, journal = {J Clin Invest}, volume = {128}, year = {2018}, month = {2018 May 01}, pages = {1807-1819}, abstract = {

Fibrosis is a prevalent pathological condition arising from the chronic activation of fibroblasts. This activation results from the extensive intercellular crosstalk mediated by both soluble factors and direct cell-cell connections. Prominent among these are the interactions of fibroblasts with immune cells, in which the fibroblast-mast cell connection, although acknowledged, is relatively unexplored. We have used a Tg mouse model of skin fibrosis, based on expression of the transcription factor Snail in the epidermis, to probe the mechanisms regulating mast cell activity and the contribution of these cells to this pathology. We have discovered that Snail-expressing keratinocytes secrete plasminogen activator inhibitor type 1 (PAI1), which functions as a chemotactic factor to increase mast cell infiltration into the skin. Moreover, we have determined that PAI1 upregulates intercellular adhesion molecule type 1 (ICAM1) expression on dermal fibroblasts, rendering them competent to bind to mast cells. This heterotypic cell-cell adhesion, also observed in the skin fibrotic disorder scleroderma, culminates in the reciprocal activation of both mast cells and fibroblasts, leading to the cascade of events that promote fibrogenesis. Thus, we have identified roles for PAI1 in the multifactorial program of fibrogenesis that expand its functional repertoire beyond its canonical role in plasmin-dependent processes.

}, issn = {1558-8238}, doi = {10.1172/JCI99088}, author = {Pincha, Neha and Hajam, Edries Yousaf and Badarinath, Krithika and Batta, Surya Prakash Rao and Masudi, Tafheem and Dey, Rakesh and Andreasen, Peter and Kawakami, Toshiaki and Samuel, Rekha and George, Renu and Danda, Debashish and Jacob, Paul Mazhuvanchary and Jamora, Colin} }