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Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF- hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced [(S100A8/ S100A9).sub.2] tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-[alpha]-driven fatal inflammation, as shown by lack of tetramer formation in crossing [S100A9.sup.-/-] mice with 2 independent TNF-[alpha]-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects., Introduction The term 'sterile inflammation' describes inflammatory processes not triggered by microbial agents (1, 2), but rather induced by endogenous molecules released during tissue damage or cell stress (3). For [...]

Mechanisms linking innate immunity and autoimmune responses are poorly understood (1). Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive [CD8.sup.+] T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of [CD8.sup.+] T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity., The pathomechanisms underlying the loss of self tolerance in autoimmunity remain largely unknown. CD40-CD40 ligand (CD40L) signaling between autoantigen-presenting dendritic cells and T cells has a major role during autoimmune [...]

Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin [alpha]4 and small amounts of laminin [alpha]5. In mice lacking laminin [alpha]4, laminin [alpha]5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin [alpha]5 directly inhibited integrin [alpha].sub.6][beta].sub.1] migration of T lymphocytes through laminin [alpha]4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population., During leukocyte extravasation into inflamed tissues, cells quickly traverse the endothelial cell monolayer where they subsequently face the endothelial basement membrane. Previous data has shown that although Leukocyte transmigration of [...]

Regulatory CD4[sup.+]CD25[sup.+] T cells are important in suppressing immune responses. The requirements for the maintenance of peripheral CD4[sup.+]CD25[sup.+] T cells remain incompletely understood. Receptor activator of NF-[kappa]B (RANK) and its ligand (RANKL; also known as CD254, OPGL and TRANCE) are key regulators of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication. Here we report that RANKL is expressed in keratinocytes of the inflamed skin. RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4[sup.+]CD25[sup.+] T cells. Thus, epidermal RANKL expression can change dendritic cell functions to maintain the number of peripheral CD4[sup.+]CD25[sup.+] regulatory T cells. Epidermal RANKL mediated ultraviolet-induced immunosuppression and overexpression of epidermal RANKL suppressed allergic contact hypersensitivity responses and the development of systemic autoimmunity. Therefore, environmental stimuli at the skin can rewire the local and systemic immune system by means of RANKL., Author(s): Karin Loser [1, 2]; Annette Mehling [1]; Stefanie Loeser [3]; Jenny Apelt [1]; Annegret Kuhn [4]; Stephan Grabbe [5]; Thomas Schwarz [6]; Josef M Penninger [3]; Stefan Beissert (corresponding [...]