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The interleukin (IL)-17 family includes six structure-related cytokines (A-F). To date, majority of studies have focused on IL-17A. IL-17A plays a pivotal role in various infectious diseases, inflammatory and autoimmune disorders, and cancer. Several recent studies have indicated that IL-17A is a biomarker as well as a therapeutic target in sepsis. In the current review, we summarize the biological functions of IL-17, including IL-17-mediated responses and signal transduction pathways, with particular emphasis on clinical relevance to sepsis.

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| INTRODUC TI ONCD4 + CD25 + regulatory T cells (Tregs) can regulate host responses to infections and tumours, and contribute to the prevention of allergies, autoimmune diseases and transplant rejection. 1-4 CD4 + CD25 + Tregs are essential for maintenance of immune homeostasis and self-tolerance. They express several crucial molecular markers, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also termed CD152), glucocorticoid-induced tumour necrosis factor receptor (GITR) and forkhead/winged helix transcription factor p3 (Foxp3).Knockdown of these factors leads to lethal lymphoproliferative phenotypes. 5-8 Concomitantly, CD4 + CD25 + Tregs can produce various potent anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor (TGF)-β, which cause immunosuppression of effector T cells. 9-12 Moreover, CD4 + CD25 + Tregs can reduce IL-2 production and inhibit polyclonal T cell activity in vitro, 13 and Abstract Naturally occurring CD4 + CD25 + regulatory T cells (Tregs) are required to limit immune-induced pathology and to maintain homeostasis during the early-phase of sepsis. This study aimed to investigate the role of interleukin (IL)-38, a newly described member of the IL-1 cytokine family, in mediated immune response of CD4 + CD25 + Tregs in sepsis. Here, we provide evidence that expressions of IL-38 and its receptor were detected in murine CD4 + CD25 + Tregs. Stimulation of CD4 + CD25 + Tregs with LPS markedly up-regulated the expression of IL-38. Treatment with rmIL-38 dramatically enhanced the immunosuppressive activity of CD4 + CD25 + Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti-IL-38 antibody was administered. Administration of rmIL-38 improved the survival rate of CLP mice. In addition, CD4 + CD25 + Tregs depletion before the onset of sepsis obviously abolished IL-38-mediated protective response. These findings suggest that IL-38 enhances the immunosuppressive activity of CD4 + CD25 + Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis. K E Y W O R D Simmune response, interleukin-38, regulatory T cells, sepsis

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

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Interleukin (IL)-34 is a cytokine discovered a few years ago and identified as the second colony-stimulating factor (CSF)-1 receptor (CSF-1R) ligand. Although CSF-1 and IL-34 share the same receptor through which they trigger similar effects, IL-34 also binds to receptors protein-tyrosine phosphatase (PTP)-ζ and syndecan-1. Thus, IL-34 is involved in several signaling pathways and participates in a wide array of biological actions. This review analyzes current studies on the role of IL-34 under physiological and pathological conditions, and explores its potential significance as a disease biomarker and therapeutic target. In physiological conditions, IL-34 expression is restricted to the microglia and Langerhans cells, with a fundamental role in cellular differentiation, adhesion and migration, proliferation, metabolism, and survival. It is released in response to inflammatory stimuli, such as pathogen-associated molecular patterns or pro-inflammatory cytokines, with effects over various immune cells, including monocytes, macrophages, and regulatory T cells that shape the immune microenvironment. Over the past decade, accumulating evidence has suggested a potent immune regulation of IL-34 in pathological states such as autoimmune diseases, cancer, transplant rejection, neurologic diseases, infections, and inflammatory diseases. Importantly, IL-34 may hold great promise for acting as a biomarker for monitoring disease severity and progression, and may serve as a new therapeutic target for the treatment of several diseases in clinical settings.

Interleukin- (IL-) 38 is an emerging cytokine with multiple functions involved in infection and immunity. However, the potential role of IL-38 in the host immune response during sepsis remains elusive. Herein, we investigated if macrophages in septic mice express IL-38, the molecular mechanisms behind its expression, and the downstream effects of its expression. In mouse peritoneal macrophages, lipopolysaccharide (LPS) upregulated IL-38 and its receptor IL-36R, and the resulting IL-38 shifted macrophages from a M1 to M2 phenotype. Moreover, exposure to IL-38 alone was sufficient to inhibit macrophage apoptosis and LPS-driven activation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome. These effects were partly abrogated by IL-38 downregulation. In septic mice, IL-38 markedly lowered serum concentrations of proinflammatory cytokines and greatly improved survival. Conversely, IL-38 blockade aggravated their mortality. Collectively, these findings present IL-38 as a potent immune modulator that restrains the inflammatory response by suppressing macrophage apoptosis and activation of the NLRP3 inflammasome. IL-38 may help protect organs from sepsis-related injury.