Abstract
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.
Highlights
Despite the progress with antimicrobial agents and modern medical techniques, sepsis remains a devastating syndrome and the major cause of mortality among intensive care unit patients [1]
We previously found that IL-38 is expressed in mouse CD4+CD25+ regulatory T cells and is upregulated upon exposure to inflammatory stimuli [19]
We explored the expression of IL-38 and its receptor IL-36 receptor (IL-36R) in mouse macrophages under inflammatory conditions
Summary
Despite the progress with antimicrobial agents and modern medical techniques, sepsis remains a devastating syndrome and the major cause of mortality among intensive care unit patients [1]. Despite the development of novel drug candidates [3, 4], the majority of clinical trials for sepsis treatment have failed, and therapeutic options for sepsis remain limited. Cytokines are crucial players in the host immune response, so an in-depth understanding of cytokinemediated immune responses during sepsis may provide hope for novel immune regulatory therapies [5]. We reviewed the substantial progress in understanding how interleukin- (IL-) 1 family of cytokines contributes to the development of sepsis [6]. These cytokines act as endogenous innate immune signals during the host response. The work from our laboratory [12] and others [13] has shown that IL-36 can greatly enhance the host immune response and improve prognosis of septic mice
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