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Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a prosthetic group of hemoproteins, such as hemoglobin and myoglobin. When released from damaged red blood cells or muscle cells, oxidized hemoglobin and myoglobin release their prosthetic heme groups, respectively. This generates labile heme, which is sensed by pattern recognition receptors (PRR) expressed by innate immune cells and possibly regulatory T cells (TREG). The ensuing adaptive response, which alerts for the occurrence of red blood cell or muscle cell damage, regulates the pathologic outcome of hemolysis or rhabdomyolysis, respectively. In conclusion, we propose that labile heme is an alarmin., (Copyright © 2015. Published by Elsevier Ltd.)

The nurse cell (NC), formed from muscle cells upon infection with the parasitic nematode Trichinella spp. constitutes a confined habitat for muscle larvae of encapsulating species. Signaling pathway-directed analysis of microarray data allowed identification of the stage of NC cell cycle arrest as being of G1-like type, accompanied by cellular senescence. In accord with the specificity of senescent cellular systems, up-regulation of pro-inflammatory molecules was also found within the NC preparations. Potential immune-related activities associated with NCs as inferred from the aforementioned analysis, are reviewed herein. Transcriptional data suggest that the NC which harbors the larvae may exhibit the following immune-related functions: (i) production of complement components, (ii) antigen presentation and phagocytosis, (iii) pro-inflammatory cytokine secretion, (iv) oxidative stress generation and (v) eicosanoid synthesis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

High titer autoantibodies, which are often associated with specific clinical phenotypes, are useful diagnostically and prognostically in systemic autoimmune diseases. In several autoimmune rheumatic diseases (e.g. myositis and Sjogren's syndrome), 20-40% of patients are autoantibody negative as assessed by conventional assays. The recent discovery of new specificities (e.g., anti-MDA5) in a subset of these autoantibody-negative subjects demonstrates that additional specificities await identification. In this manuscript, we describe a rapid multidimensional method to identify new autoantigens. A central foundation of this rapid approach is the use of an antigen source in which a pathogenic pathway active in the disease is recapitulated. Additionally, the method involves a modified serological proteome analysis strategy which allows confirmation that the correct gel plug has been removed prior to sending for sequencing. Lastly, the approach uses multiple sources of information to enable rapid triangulation and identification of protein candidates. Possible permutations and underlying principles of this triangulation strategy are elaborated to demonstrate the broad utility of this approach for antigen discovery., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Inflammatory myopathies (IMs) are systemic diseases characterized by a T helper (Th) 1 type inflammatory response and cell infiltrates within skeletal muscles. The mainstay of treatment is drugs aimed at suppressing the immune system - corticosteroids and immunosuppressants. About 25% of patients are non-responders. Skeletal muscle cells seem actively involved in the immune-inflammatory response and not only a target; understanding the molecular bases of IMs might help drug development strategies. Within muscles the interaction between the chemokine interferon (IFN)γ inducible 10 kDa protein, CXCL10 or IP-10, and its specific receptor CXCR3, present on Th1 type infiltrating cells, likely plays a pivotal role, potentially offering the opportunity for therapeutic intervention. We aimed to clarify the involvement of human skeletal muscle cells in inflammatory processes in terms of CXCL10 secretion, to elucidate the engaged molecular mechanism(s) and, finally, to evaluate muscular cell responses, if any, to some immunosuppressants routinely used in IM treatment, such as methylprednisolone, methotrexate, cyclosporin A and Infliximab. We first isolated and characterized human fetal skeletal muscle cells (Hfsmc), which expressed the specific lineage markers and showed the competence to react in the context of an in vitro alloresponse. CXCL10 protein secretion by Hfsmc was similarly induced by the inflammatory cytokines interferon (IFN)γ and tumor necrosis factor (TNF)α, above undetectable control levels, through the activation of Stat1 and NF-kB pathways, respectively; CXCL10 secretion was significantly magnified by cytokine combination, and this synergy was associated to a significant up-regulation of TNFαRII; cytokine-induced CXCL10 secretion was considerably affected only by Infliximab. Our data suggested that human skeletal muscle cells might actively self-promote muscular inflammation by eliciting CXCL10 secretion, which is known to amplify Th1 cell tissue infiltration in vivo. In conclusion, we sustain that pharmacological targeting of CXCL10 within muscular cells might contribute to keep in control pro-Th1 polarization of the immune/inflammatory response., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Sepsis is associated with ventricular dysfunction and increased incidence of atrial and ventricular arrhythmia however the underlying pro-arrhythmic mechanisms are unknown. Serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are elevated during sepsis and affect Ca2+ regulation. We investigated whether pro-inflammatory cytokines disrupt cellular Ca2+ cycling leading to reduced contractility, but also increase the probability of pro-arrhythmic spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). Isolated rat ventricular myocytes were exposed to TNF-alpha (0.05 ng ml(-1)) and IL-1beta (2 ng ml(-1)) for 3 hr and then loaded with fura-2 or fluo-3 to record the intracellular Ca2+ concentration ([Ca2+](i)). Cytokine treatment decreased the amplitude of the spatially averaged Ca2+ transient and the associated contraction, induced asynchronous Ca2+ release during electrical stimulation, increased the frequency of localized Ca2+ release events, decreased the SR Ca2+ content and increased the frequency of spontaneous Ca2+ waves at any given cytoplasmic Ca2+. These data suggest that TNF-alpha and IL-1beta increase the SR Ca2+ leak from the SR, which contributes to the depressed Ca2+ transient and contractility. Increased susceptibility to spontaneous SR Ca2+ release may contribute to arrhythmias in sepsis as the resulting Ca2+ extrusion via NCX is electrogenic, leading to cell depolarisation., (2010 Elsevier Ltd. All rights reserved.)