Sensing intracellular pathogens is a process mediated by innate immune cells that is crucial for the induction of inflammatory processes and effective adaptive immune responses against pathogenic microbes. NOD-like receptors (NLRs) comprise a family of intracellular pattern recognition receptors that are important for the recognition of damage and microbial-associated molecular patterns. NOD1 and NOD2 are specialized NLRs that participate in the recognition of a subset of pathogenic microorganisms that are able to invade and multiply intracellularly. Once activated, these molecules trigger intracellular signaling pathways that lead to the activation of transcriptional responses culminating in the expression of a subset of inflammatory genes. In this review, we will focus on the role of NOD1 and NOD2 in the recognition and response to intracellular pathogens, including Gram-positive and Gram-negative bacteria, and on their ability to signal in response to non-peptidoglycan-containing pathogens, such as viruses and protozoan parasites.

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SummarySystemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCWmediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro-and anti-inflammatory responses to Gram-positive bacteria.

Extensive apoptosis of leukocytes during sepsis and endotoxic shock constitutes an important mechanism linked to the excessive mortality associated with these disorders. Caspase inhibitors confer protection from endotoxin-induced lymphocyte apoptosis and improve survival, but it is not clear which caspases mediate lipopolysaccharide (LPS)-induced lymphocyte apoptosis and mortality. We report here that the apoptotic executioner caspase-7 was activated in the splenocytes of LPS-injected mice, suggesting a role for caspase-7 in lymphocyte apoptosis. Indeed, caspase-7-deficient mice were resistant to LPS-induced lymphocyte apoptosis and were markedly protected from LPS-induced lethality independently of the excessive production of serum cytokines. These results reveal for the first time a nonredundant role for caspase-7 in vivo and identify caspase-7 inhibition as a component of the mechanism by which caspase inhibitors protect from endotoxin-induced mortality. (Blood. 2009;113:2742-2745) IntroductionSepsis is the most common cause of mortality in patients treated in the intensive care setting, with more than 210 000 sepsis-related deaths occurring annually in the United States. 1 Extensive apoptotic death of leukocytes is commonly observed in patients who died of sepsis 2,3 and was suggested to contribute significantly to immune suppression and lethality. [4][5][6][7][8] In this regard, synthetic caspase inhibitors and overexpression of the antiapoptotic protein Bcl-2 were shown to diminish lymphocyte apoptosis and improve survival in experimental sepsis models. [8][9][10][11][12] However, it is currently incompletely understood which caspases promote lymphocyte apoptosis and contribute to lethality.Together with caspase-3, the executioner caspase-7 performs central roles in the execution phase of apoptosis by cleaving a large set of substrates, ultimately resulting in the morphologic and biochemical hallmarks of apoptosis such as DNA fragmentation. [13][14][15][16] Caspase-3/-7 double-deficient mice were recently shown to exhibit embryonic lethality, whereas mice singly deficient in either caspase are born at normal Mendelian ratios and display no gross abnormalities when maintained on a C57BL/6 genetic background. 17 At this stage, the precise roles of caspase-7 in the adult animals remain to be elucidated.In this study, we show that caspase-7 was activated in splenocytes of lipopolysaccharide (LPS)-treated mice and that caspase-7 Ϫ/Ϫ mice were protected from LPS-induced splenocyte apoptosis. As a result, caspase-7 deficiency improved survival during endotoxemia without affecting cytokine levels. Methods MiceCaspase-1 Ϫ/Ϫ , caspase-3 Ϫ/Ϫ , and caspase-7 Ϫ/Ϫ mice were backcrossed to C57BL/6 background for 10 generations and have been described previously. 17,18 Mice were originally purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in a pathogen-free facility. The animal studies were conducted under protocols approved by St Jude Children's Research Hospital Committee on Use and Care of Animals. LPS-...

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen able to survive and multiply within macrophages. Several mechanisms allow this bacterium to escape macrophage microbicidal activity. Mtb may interfere with the ability of mouse macrophages to produce antibactericidal nitric oxide, by inducing the expression of arginase 1 (Arg1). It remains unclear whether this pathway has a role in humans infected with Mtb. In this study, we investigated the expression of Arg1 in granulomas of human lung tissues from patients with tuberculosis. We show that Arg1 is expressed not only in granuloma‐associated macrophages, but also in type II pneumocytes.