Rheumatic diseases are characterized by sterile inflammation that causes severe long-term damage to various organ systems. A growing body of evidence supports a pivotal role for the pro-inflammatory calcium-binding S100 family of proteins in the pathogenesis of rheumatic diseases. Some S100 proteins are released at the site of inflammation and act as danger-associated molecular pattern molecules by activating pattern recognition receptors. Increased concentrations of S100 proteins in serum and synovial fluid closely correlate with disease activity in several rheumatic diseases and serve as useful biomarkers for monitoring disease activity. Some S100 proteins are also valid biomarkers for predicting response to treatment, systemic organ involvement or disease flares in rheumatic diseases. Analyses of knockout mouse models have confirmed a functional role for S100 proteins, particularly S100A8 and S100A9, in rheumatic diseases, indicating that blocking the expression, release or function of these proteins might be an innovative therapeutic strategy. Owing to their local pattern of expression, specific mechanism of release and autoregulatory effects, such therapeutic approaches would primarily target the local inflammatory process and present only minor risks of systemic adverse effects.

The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products–dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response.

Sarcoidosis, a chronic, inflammatory disease that affects various different organs, is characterized by noncaseating epitheloid granulomas. This systemic inflammatory process is associated with an increased risk of cancer. Several cases of sarcoidosis that mimic metastatic tumor progression in radiological findings have been reported so far. However, there are also cases that have presented a coexistence of sarcoidosis and metastasis, which have caused a diagnostic and therapeutic dilemma. Due to inadequate current therapies, a reliable differentiation between benign and malignant lesions is crucial. This review focuses on the residual risk of the coexistence of metastases within radiological suspicious lesions in patients with a history of solid tumors and sarcoidosis, as well as immunological findings, in order to explain the potential associations. Sarcoidosis has the potential to promote metastasis as it includes tumor-promoting and immune-regulating cell subsets. Notably, myeloid derived suppressor cells may serve a pivotal role in metastatic progression in patients with sarcoidosis. In addition, the present review also evaluates the potential novel diagnostic approaches, which may be able to differentiate between metastatic lesions and sarcoidosis. The risk of coexistent metastasis in sarcoidosis lesions must be considered by clinical practitioners, and a multidisciplinary approach may be required to avoid misdiagnosis and the subsequent unnecessary surgery or insufficient treatments.

Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches. We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo.Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18- as well as MRP14-deficient mice. A VLA4α-/- cell line was generated by CRISPR/Cas9-mediated gene editing. We analyzed the migration of wildtype and knockout leukocytes in vivo by optical and nuclear imaging in mice with irritant contact dermatitis, cutaneous granuloma, experimental arthritis and myocardial infarction.Results: Transient immortalization, gene editing and in vivo imaging can be combined to analyze migratory mechanisms of murine leukocytes, even for gene deletions resulting in lethal phenotypes in mice. We reliably confirmed known migratory defects of leukocytes deficient for the adhesion molecules CD18 or VLA4α. Also, using our new method we identified a new role of the most abundant calcium-binding proteins in phagocytes and major alarmins in many inflammatory diseases, MRP8 and MRP14, for transmigration in vivo.Conclusion: We provide a combinatorial approach to rapidly characterize molecular mechanisms of leukocyte recruitment in vivo, with the potential to aid in identification of diagnostic and therapeutic targets in inflammatory pathologies.

Influence of environmental temperature on the occurrence of non-necrotizing cellulitis of the leg SIR, Non-necrotizing cellulitis of the leg is a common cutaneous bacterial infection whose risk factors include venous insufficiency, lymphoedema and toe-web intertrigo. The role of environmental temperature remains controversial. 1 To study the relationship between environmental temperature and the frequency of non-necrotizing cellulitis of the leg, we reviewed all patients hospitalized with nonnecrotizing cellulitis of the leg in a university hospital in a temperate region of France during a 4-year period, and correlated findings with the local environmental temperature during the same period.Patients included in this study were consecutive patients referred for non-necrotizing cellulitis of the leg from January 1995 to December 1998 in the Departments of Dermatology, Internal Medicine and Infectious Diseases of the Rouen University Hospital. The diagnosis of cellulitis of the leg was retrospectively identified using the database of the Medical Information System. The mean and maximum temperatures of each the 8 days prior to the date of hospital admission were obtained from the local meteorological unit for each case. Correlations between the mean and maximum daily temperature of each day from day ) 8 to the admission day (lag 0-8 days) and the daily number of patients hospitalized for cellulitis of the leg were studied using a nonparametric Poisson regression model to adjust for time trends and days of the week (generalized additive model). 2 Eight hundred and ninety-eight patients with cellulitis of the leg [342 men (38%) and 556 women (62%)] were