Dragos Dasoveanu

A Dendritic-Cell-Stromal Axis Maintains Immune Responses in Lymph Nodes

Within secondary lymphoid tissues, stromal reticular cells support lymphocyte function, and targeting reticular cells is a potential strategy for controlling pathogenic lymphocytes in disease. However, the mechanisms that regulate reticular cell function are not well understood. Here we found that during an immune response in lymph nodes, dendritic cells (DCs) maintain reticular cell survival in multiple compartments. DC-derived lymphotoxin beta receptor (LTβR) ligands were critical mediators, and LTβR signaling on reticular cells mediated cell survival by modulating podoplanin (PDPN). PDPN modulated integrin-mediated cell adhesion, which maintained cell survival. This DC-stromal axis maintained lymphocyte survival and the ongoing immune response. Our findings provide insight into the functions of DCs, LTβR, and PDPN and delineate a DC-stromal axis that can potentially be targeted in autoimmune or lymphoproliferative diseases.

Multiple CD11c+ Cells Collaboratively Express IL-1β To Modulate Stromal Vascular Endothelial Growth Factor and Lymph Node Vascular–Stromal Growth

Lymphadenopathy in autoimmune and other lymphoproliferative diseases is in part characterized by immunoblasts and vascular proliferation. The lymph node vasculature, along with the nonvascular stromal compartment, supports lymphocyte function, and targeting vascular–stromal expansion in inflamed nodes may modulate lymphocyte function in disease. CD11c+ cells are essential for vascular–stromal proliferation and the upregulation of vascular endothelial growth factor (VEGF) needed for vascular proliferation. However, targetable CD11c+ cell–derived molecular mediators, the identity of relevant CD11c+ cells, and whether CD11c+ cells directly stimulate VEGF-expressing stromal cells are poorly understood. In this study we show that CD11c+ CD11b+ CCR2-dependent monocytes and CCR7-dependent dendritic cells express IL-1β. IL-1β blockade, IL-1β deficiency in radiosensitive cells, and CCR2/CCR7 double deficiency but not single deficiency all attenuate immunization-induced vascular–stromal proliferation. gp38+ stromal fibroblastic reticular cells (FRCs) that express VEGF are enriched for Thy1+ cells and partially overlap with CCL21-expressing FRCs, and FRC VEGF is attenuated with IL-1β deficiency or blockade. IL-1β localizes to the outer borders of the T zone, where VEGF-expressing cells are also enriched. Ex vivo, CD11b+ cells enriched for IL-1β+ cells can directly induce cultured gp38+Thy1+ FRCs to upregulate VEGF. Taken together, these results suggest a mechanism whereby multiple recruited CD11c+ populations express IL-1β and directly modulate FRC function to help promote the initiation of vascular–stromal growth in stimulated lymph nodes. These data provide new insight into how CD11c+ cells regulate the lymph node vascular–stromal compartment, add to the evolving understanding of functional stromal subsets, and suggest a possible utility for IL-1β blockade in preventing inflammatory lymph node growth.

Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis

Scleroderma is a group of skin-fibrosing diseases for which there are no effective treatments. A feature of the skin fibrosis typical of scleroderma is atrophy of the dermal white adipose tissue (DWAT). Adipose tissue contains adipose-derived mesenchymal stromal cells (ADSCs) that have regenerative and reparative functions; however, whether DWAT atrophy in fibrosis is accompanied by ADSC loss is poorly understood, as are the mechanisms that might maintain ADSC survival in fibrotic skin. Here, we have shown that DWAT ADSC numbers were reduced, likely because of cell death, in 2 murine models of scleroderma skin fibrosis. The remaining ADSCs showed a partial dependence on dendritic cells (DCs) for survival. Lymphotoxin β (LTβ) expression in DCs maintained ADSC survival in fibrotic skin by activating an LTβ receptor/β1 integrin (LTβR/β1 integrin) pathway on ADSCs. Stimulation of LTβR augmented the engraftment of therapeutically injected ADSCs, which was associated with reductions in skin fibrosis and improved skin function. These findings provide insight into the effects of skin fibrosis on DWAT ADSCs, identify a DC-ADSC survival axis in fibrotic skin, and suggest an approach for improving mesenchymal stromal cell therapy in scleroderma and other diseases.

Regulation of Lymph Node Vascular–Stromal Compartment by Dendritic Cells

During normal and pathologic immune responses, lymph nodes can swell considerably. The lymph node vascular-stromal compartment supports and regulates the developing immune responses and undergoes dynamic expansion and remodeling. Recent studies have shown that dendritic cells (DCs), best known for their antigen presentation roles, can directly regulate the vascular-stromal compartment, pointing to a new perspective on DCs as facilitators of lymphoid tissue function. Here, we review the phases of lymph node vascular-stromal growth and remodeling during immune responses, discuss the roles of DCs, and discuss how this understanding can potentially be used for developing novel therapeutic approaches.

Tertiary lymphoid organs in systemic autoimmune diseases: pathogenic or protective?

Tertiary lymphoid organs are found at sites of chronic inflammation in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. These organized accumulations of T and B cells resemble secondary lymphoid organs and generate autoreactive effector cells. However, whether they contribute to disease pathogenesis or have protective functions is unclear. Here, we discuss how tertiary lymphoid organs can generate potentially pathogenic cells but may also limit the extent of the response and damage in autoimmune disease.

A protective Langerhans cell–keratinocyte axis that is dysfunctional in photosensitivity

Langerhans cells limit ultraviolet radiation–induced keratinocyte apoptosis and skin injury, and this axis is dysfunctional in lupus photosensitivity. Abrogating keratinocyte apoptosis in lupus Lupus patients can experience photosensitivity as manifested by joint pain, fatigue, and skin rashes. To better understand the mechanisms behind this photosensitivity, Shipman et al. examined patient skin samples and mouse models of lupus. They saw that, in healthy mice and human skin exposed to ultraviolet radiation, Langerhans cells protected keratinocytes from apoptosis through a mechanism involving the metalloproteinase ADAM17 and EGFR ligands. In the lupus mice and patient samples, the Langerhans cells were unable to do this. Stimulating EGFR in the skin may bring relief to photosensitive lupus patients. Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)–keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin–diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.