IntroductionTraditionally associated with the allergic response, mast cells (MCs) are now viewed as important players in a variety of immune processes, such as pathogen clearance, graft acceptance, tumor immunity, and many inflammatory and autoimmune diseases, where they exhibit either pro-or anti-inflammatory potential depending on the context. 1 Interactions of MCs with T cells have a functional role in some T cell-mediated pathologies, such as neutrophilic airway inflammation, 2,3 and autoimmune disease of the central nervous system (CNS). 4 MC-deficient mouse models show reduced development of both allergic and neutrophilic airway hyperreactivity (AHR). 2,3 MCderived tumor necrosis factor-␣ (TNF-␣) is required for T helper cell (Th17) development in the lung on ovalbumin (OVA) challenge of OTII transgenic mice, 3 a neutrophilic AHR model strictly dependent on interleukin-17 (IL-17). 5 In multiple sclerosis, MCs colocalize with demyelinating plaques in inflamed brain, and many MC-associated markers have been detected in the affected tissue. 6 The MC-deficient strain Kit W/W-v shows decreased incidence and severity of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis. 7 MCs could be directly activated during EAE by either the specific myelin peptides or locally released agonists, including complement, cytokines, and neuropeptides, but also indirectly stimulated via Fc⑀RI by specific IgE elicited on activation of Th2 response. 1,8 In the CNS, the local release of inflammatory cytokines, proteases, oxygen radicals, and chemokines by MCs directly contributes to myelin degradation, disruption of the blood-brain barrier, and recruitment and activation of other immune cells as T lymphocytes and granulocytes in the brain parenchyma, thus exacerbating the effector phase of autoimmune response. 4 MCs are also thought to be involved in initiating EAE, through the interaction with dendritic cells and T cells in secondary lymphoid organs. 9 IL-17-secreting Th17 are considered one of the major pathogenic immune components in both EAE 10 and neutrophilic AHR. 3 Th17 cells differentiate from uncommitted precursors on antigenic activation and costimulation in the concomitant presence of a suppressive and a pro-inflammatory signal delivered by transforming growth factor-␤ (TGF-␤) and IL-6 and/or IL-21, respectively. Once primed in lymph nodes, pathogenic Th17 cells reach the inflamed tissue where they recruit granulocytes and intensify inflammation. 11 Regulatory T cells (Tregs) are one of the most relevant sources of TGF-␤ both in vitro and in vivo. This CD4 ϩ T lymphocyte subset, characterized by the constitutive expression of several costimulatory molecules and the transcription factor Foxp3, is endowed with immune-suppressive properties necessary to induce and maintain tolerance. 12 Recent findings support the notion of Treg plasticity in vivo because inflammatory stimuli can counteract Treg suppression and even promote differentiation into pathogenic Th17 cells. 13 MCs may directly or...

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. Tirone et al. show that alternative redox forms of high mobility group box 1 (HMGB1), the “alarmin” signal released by damaged cells, trigger inflammation or tissue repair after injury by interacting with distinct receptors and that a nonoxidizable HMGB1 mutant promotes regeneration without exacerbating inflammation.

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Histones are the protein component of nucleosomes, which are the basic packing unit of chromatin. However, histones are also found in the blood, both as components of nucleosomes leaked out from dead cells, or expelled from neutrophils in the active process of NET formation. Circulating histones contribute to inflammation, and to lethality in sepsis, a hyperinflammatory condition, by interacting with specific receptors, notably toll-like receptor 4 (TLR4). Here, we show that histones are also actively released by LPS-activated macrophages in association with extracellular vesicles. Vesicle-associated histones can be recovered from the plasma of mice with sepsis. Actively released histones are on the outer surface of vesicles and can interact with TLR4. Thus, activated macrophages release histones without dying, at the same time, making their DNA more accessible and communicating to other cells that infection is present.