Mechanisms of Tissue Injury in Lupus Nephritis Giovanna Flores-Mendoza, Stephanie P. Sansón, Santiago Rodríguez-Castro, José C. Crispín, Florencia Rosetti  Trends in Molecular Medicine  Volume 24, Issue 4, Pages 364-378 (April 2018) DOI: 10.1016/j.molmed.2018.02.003 Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 1 Immune-Mediated Tissue Damage in Lupus Nephritis For a Figure360 author presentation of Figure 1, see the figure legend at https://doi.org/10.1016/j.molmed.2018.02.003 Figure360: an author presentation of Figure 1Figure 1 (A) Deposited immune complexes (ICs) activate complement through the classical pathway. This initiates cell damage and generates chemoattractant factors (i.e., C3a and C5a), which recruit myeloid cells. ICs activate neutrophils through Fcγ receptors (FcγRs), leading to the release of reactive oxygen species (ROS), cytokine production, and degranulation. (B) IC-FcγR engagement on APCs promotes the release of proinflammatory cytokines and antigen presentation, amplifying the local immune response. (C) The inflammatory milieu causes podocyte injury and foot process effacement, proliferation of mesangial and parietal epithelial cells, increase in extracellular matrix formation and deposition that culminates in glomerular dysfunction and sclerosis. Trends in Molecular Medicine 2018 24, 364-378DOI: (10.1016/j.molmed.2018.02.003) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 2 Neutrophil Effector Functions that May Contribute to Lupus Nephritis. (A) Immune complexes (ICs) induce neutrophil activation and production of high concentrations of reactive oxygen species (ROS; partially reduced oxygen metabolites) that possess strong oxidizing capacities. These species oxidize proteins and lipids and damage DNA. Neutrophil activation also promotes the upregulation of induced nitric oxide synthase (iNOS), an enzyme that produces nitric oxide (NO), promoting the generation of peroxynitrites, which nitrosylate proteins in the extracellular milieu contributing to tissue injury. ROS promote cell death by interfering with the regulation of caspase-8 activation and modifying mitochondrial permeability. Neutrophil activation also leads to the formation of NETs within the kidney. (B) Fcγ receptor (FcγR)-dependent neutrophil activation induces the production and release of proinflammatory and chemoattractant proteins that amplify the inflammatory response during LN. (C) Neutrophil degranulation and release of elastase and matrix metalloproteases (MMPs) contributes directly and indirectly to tissue injury. Directly, by catalyzing the degradation of the basement membrane structural components and indirectly, by accelerating the conversion from proenzymes to active enzymes by elastase mediated-cleavage. Abbreviation: GBM, glomerular basement membrane. Trends in Molecular Medicine 2018 24, 364-378DOI: (10.1016/j.molmed.2018.02.003) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 3 Kidney Response to Chronic Inflammation. (A) Normal kidney. Pericytes contribute to the development, preservation, and remodeling of the vasculature, as well as to the regulation of blood flow and maintenance of basement membranes. (B) Injured kidney. Pericytes respond to soluble mediators released by infiltrating immune cells and injured tubular epithelial cells. Pericytes detach from capillaries, which makes capillaries unstable and prone to disappear, in a process known as capillary rarefaction. Pericyte detachment induces their differentiation into myofibroblasts, which play a major role in the development of fibrosis. Thus, pericyte damage creates a positive feedback loop of ischemia, inflammation, and fibrosis. Abbreviations: Ang-2, Angiopoietin 2; BMP-7, bone morphogenetic protein 7; CTGF, connective tissue growth factor; ECM, extracellular matrix; MMP, matrix metalloprotease; PDGFB, platelet-derived growth factor B; PDGFRB, platelet-derived growth factor receptor B; α-SMA, alpha smooth muscle actin; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; VEGF-A, vascular endothelial growth factor A; VEGFR-2, vascular endothelial growth factor receptor 2. Trends in Molecular Medicine 2018 24, 364-378DOI: (10.1016/j.molmed.2018.02.003) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 4 Functional Effects of Lupus Nephritis-Associated Genetic Variants. (A) Low copy number of FCGR3B reduces the surface expression of FcγRIIIB. This receptor has an important role in the clearance of deposited immune complexes (ICs). Therefore, its low expression could contribute to lupus nephritis by increasing the amount of glomerular ICs. (B) Mac-1 inhibits effector receptors in myeloid cells. This effect requires its full activation induced by ligand binding (i.e., physical separation of its intracellular tails). A systemic lupus erythematosus (SLE)-associated variant of ITGAM causes an important reduction of its ability to bind ligand, and therefore to negative regulate effector receptors, such as FcγRIIA. (C) The SLE-associated variant of IRF5 increases IRF-5 transcription and stability, thus enhancing its function. (D) The functional effects of the PTPN22 risk allele represents a loss-of-function mutation that reduces the activation threshold of T and B cells, promoting autoimmunity. Abbreviation: ROS, reactive oxygen species. Trends in Molecular Medicine 2018 24, 364-378DOI: (10.1016/j.molmed.2018.02.003) Copyright © 2018 Elsevier Ltd Terms and Conditions