We are interested in what mediates the scleroderma (SSc) phenotype by understanding the fibrotic and immunological events in these patients. SSc is a fibrotic disease of unknown origin that is predominantly found in women. What is apparent is the uncontrolled fibrosis in the dermis and internal organs that affects morbidity and leads to mortality in these patients. Understanding the mechanisms whereby myofibroblasts and fibroblasts interact with the extracellular matrix (ECM) is central to the understanding of fibrosis in SSc and wound healing in general. Fibroblasts are sensitive to signals from the ECM and interaction of fibroblasts with the ECM is essential in many physiological and pathological processes. Integrins are important for transferring signals from the ECM into the cell and play an important role in regulating the efficiency of the RTK/Ras/ERK pathway. 3-Deoxyglucosone (3DG) is a highly reactive α-dicarbonyl that increases with chronological age and diet, and directly cross-links long-lived proteins such as collagen. It is known that the elderly frequently have less collagen in their skin resulting in wound healing problems in some. We observed that collagen cross-linked with 3DG caused a decrease in the expression of ECM proteins in normal and SSc fibroblasts cultured in vitro. The goals are to understand the cellular signaling mechanisms whereby the collagen expression is decreased in 3DG cross-linked matrices.
The inflammasome modulates the innate immune response and may be mediating fibrosis in SSc. Activation of the inflammasome appears to be directly involved in fibrosis in the bleomycin induced fibrotic animal model of SSc. We are currently using this mouse model to study early initiating events of fibrosis and have related those events to the differentiation of fibroblasts into myofibroblasts. We have found that by deleting NLRP3 and ASC proteins from the inflammasome, we are able to inhibit fibrosis in the skin. We found the increased expression of NOD2, AIM2, and NLRP3 inflammasomes in SSc fibroblasts. In vitro studies have indicated that the inflammasome is active in SSc and is mediating the elevated levels of IL-1β and IL-18 that in turn could be controlling the expression of TGF-β1 (Figure 1). Further research has demonstrated that inhibition of caspase-1 activity ameliorated the myofibroblasts phenotype and decreased collagen secretion by these cells.
More recently my laboratory has been investigating targeting the inflammasome as a means of promoting pathogen clearance. We have been investigating a novel peptide (acALY18) that induces rapid clearance of MRSA. acALY18 activates the inflammasome and its effects can be inhibited with YVAD, a caspase-1 inhibitor. The role of acALY18 in stimulating the innate immune response is currently under investigation.
Selected publications:(See all Carol Artlett's publications in PubMed.)
"Inflammasomes in wound healing and fibrosis"
Journal of Pathology, In Press, 2012.
"Recent Advances in Scleroderma Pulmonary Fibrosis"
Advances in Medicine and Biology. Editor LA Burnhardt. Vol 53, Chapter 3, 2012.
"The law of unintended consequences and antibiotics"
Thacker JD and CM Artlett
Open Journal of Immunology, 2: 59-64, 2012.
"The role of the NLRP3 inflammasome in fibrosis"
The Open Rheumatology Journal, 6 (Suppl 1, M3): 80-86, 2012.
"NLRP3 Inflammasome is a Target for Development of Broad-Spectrum Anti-Infective Drugs"
Thacker JD, Sassi-Gaha S, Stephens C, Purohit M, Rest RF, and CM Artlett
Antimicrobial Agents and Chemotherapeutics, 56: 1921-1930, 2012.
"The Inflammasome Activating Caspase-1 Mediates Fibrosis and Myofibroblast Differentiation in Systemic Sclerosis"
Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick CA, and PD. Katsikis
Arthritis and Rheumatism, 63: 3563-3574, 2011.
Modification of collagen by 3-deoxyglucosone alters wound healing through differential regulation of p38 MAP kinase.
Loughlin DT, and Artlett CM.
PLOS One, 6:e18676, 2011.
Animal models of scleroderma: Fresh Insights.
Current Opinion in Rheumatology, 22:677-82, 2010.
Precursor of Advanced Glycation End Products 3-deoxyglucosone Mediates ER-stress-induced Caspase-3 Activation of Human Dermal Fibroblasts through NAD(P)H Oxidase 4.
Loughlin DT, and Artlett CM.
PLOS One, 5: e11093, 2010.
Two dicarbonyl compounds, 3-deoxyglucosone and methylglyoxal, differentially modulate dermal fibroblasts.
Sassi-Gaha S, Loughlin DT, Kappler F, Schwartz ML, Su Bangying, Tobia AM, and Artlett CM.
Matrix Biology, 29: 127-134, 2010.
1-peptidyl-2,3-diacryglyceride: an endogenous lipopeptide is an activator of the innate arm of the immune response.
Thacker JD, Purohit M, Sassi-Gaha S, Rest RF, and Artlett CM.
Journal of Natural Products 72: 1993-1999, 2009.
3-Deoxyglucosone-Collagen Alters Human Dermal Fibroblast Migration and Adhesion: Implications for Impaired Wound Healing in Patients with Diabetes. Wound Repair Regen.
Loughlin DT, and Artlett CM.
17: 739-749, 2009.
Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis.
Hoffman WH, Artlett CM, Zhang W, Kriepke CW, Passmore GG, Rafols JA, and Sima AA.
Brain Research, 1238: 154-162, 2008.
IL-15 treatment during acute SIV infection increases viral set point and accelerates disease progression.
Mueller YM, Duc HD, Altork SR, Artlett CM, Graceley EJ, Katsetos CD, Legido A, Villinger F, Altman JD, Brown CR, Lewis MG, and Katsikis PD.
The Journal of Immunology, 180: 350-360, 2008.
Allograft inflammatory factor-1 and tumor necrosis factor single nucleotide polymorphism in systemic sclerosis.
Otieno FG, Lopez AM, Jimenez SA, Gentiletti J, and Artlett CM.
Tissue Antigens, 69: 583-591, 2007.