• Clinical and Experimental Pediatrics
• /
• v.53 no.12
• /
• pp.985-988
• /
• 2010

The innate immune response is the first line of defense against microbial infections. Innate immunity is made up of the surface barrier, cellular immunity and humoral immunity. In newborn, immunologic function and demands are different to adults. Neonatal innate immunity specifically suppresses Th1-type immune responses, and not Th2-type immune responses, which are enhanced. And the impaired response of macrophages is associated with the defective innate immunity in newborn period. Toll-like receptors (TLRs) play a key roles in the detection of invading pathogens and in the induction of innate immune responses. In newborn, the expression of TLRs is age dependent, so preterm has low expression of TLRs. Also, there are defects in signaling pathways downstream of TLRs. As a consequence, the defects of TLRs activity cause the susceptibility to infection in the neonatal period.

• Molecules and Cells
• /
• v.42 no.1
• /
• pp.1-7
• /
• 2019

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.

• Journal of Microbiology and Biotechnology
• /
• v.30 no.11
• /
• pp.1626-1639
• /
• 2020

In Caenorhabditis elegans, SHN-1 is the homologue of SHANK, a scaffolding protein. In this study, we determined the molecular basis for SHN-1/SHANK in the regulation of innate immune response to fungal infection. Mutation of shn-1 increased the susceptibility to Candida albicans infection and suppressed the innate immune response. After C. albicans infection for 6, 12, or 24 h, both transcriptional expression of shn-1 and SHN-1::GFP expression were increased, implying that the activated SHN-1 may mediate a protection mechanism for C. elegans against the adverse effects from fungal infection. SHN-1 acted in both the neurons and the intestine to regulate the innate immune response to fungal infection. In the neurons, GLR-1, an AMPA ionotropic glutamate receptor, was identified as the downstream target in the regulation of innate immune response to fungal infection. GLR-1 further positively affected the function of SER-7-mediated serotonin signaling and antagonized the function of DAT-1-mediated dopamine signaling in the regulation of innate immune response to fungal infection. Our study suggests the novel function of SHN-1/SHANK in the regulation of innate immune response to fungal infection. Moreover, our results also denote the crucial role of neurotransmitter signals in mediating the function of SHN-1/SHANK in regulating innate immune response to fungal infection.

• Animal cells and systems
• /
• v.13 no.1
• /
• pp.1-8
• /
• 2009

Toll-like receptor (TLR) family proteins, type I transmembrane proteins, play a central role in human innate immune response by recognizing common structural patterns in diverse molecules from bacteria, viruses and fungi. Recently four structures of the TLR and ligand complexes have been determined by high resolution x-ray crystallographic technique. In this review we summarize reported structures of TLRs and their proposed activation mechanisms. The structures demonstrate that binding of agonistic ligands to the extracellular domains of TLRs induces homo- or heterodimerization of the receptors. Dimerization of the TLR extracellular domains brings their two C-termini into close proximity. This suggests a plausible mechanism of TLR activation: ligand induces dimerization of the extracellular domains, which enforces juxtaposition of intracellular signaling domains for recruitment of intracellular adaptor proteins for signal initiation.

• IMMUNE NETWORK
• /
• v.11 no.4
• /
• pp.223-226
• /
• 2011

Although exercise-induced growth factors such as Insulin-like growth factor-I (IGF-I) are known to affect various aspects of physiology in skeletal muscle cells, the molecular mechanism by which IGF-I modulates anti-inflammatory effects in these cells is presently unknown. Here, we showed that IGF-I stimulation suppresses the expression of toll-like receptor 4 (TLR4), a key innate immune receptor. A pharmacological inhibitor study further showed that PI3K/Akt signaling pathway is required for IGF-I-mediated negative regulation of TLR4 expression. Furthermore, IGF-I treatment reduced the expression of various NF-${\kappa}B$-target genes such as TNF-${\alpha}$ and IL-6. Taken together, these findings indicate that the anti-inflammatory effect of exercise may be due, at least in part, to IGF-I-induced suppression of TLR4 and subsequent downregulation of the TLR4-dependent inflammatory signaling pathway.

• Molecules and Cells
• /
• v.44 no.5
• /
• pp.335-341
• /
• 2021

Zinc is an essential micronutrient with crucial roles in multiple facets of biological processes. Dysregulated zinc homeostasis impairs overall immune function and resultantly increases susceptibility to infection. Clinically, zinc supplementation is practiced for treatment of several infectious diseases, such as diarrhea and malaria. Recent focus on zinc as a beneficial element for immune system support has resulted in investigation of the immunomodulatory roles of zinc in a variety of immune cells. Besides its classical role as a cofactor that regulates the structural function of thousands of proteins, accumulating evidence suggests that zinc also acts, in a manner similar to calcium, as an ionic regulator of immune responses via participation as an intracellular messenger in signaling pathways. In this review, we focus on the role of zinc as a signaling molecule in major pathways such as those downstream of Toll-like receptors-, T cell receptor-, and cytokine-mediated signal transduction that regulate the activity and function of monocytes/macrophages and T cells, principal players in the innate and adaptive immune systems.

• IMMUNE NETWORK
• /
• v.14 no.6
• /
• pp.307-320
• /
• 2014

Mycobacterium scrofulaceum is an environmental and slow-growing atypical mycobacterium. Emerging evidence suggests that M. scrofulaceum infection is associated with cervical lymphadenitis in children and pulmonary or systemic infections in immunocompromised adults. However, the nature of host innate immune responses to M. scrofulaceum remains unclear. In this study, we examined the innate immune responses in murine bone marrow-derived macrophages (BMDMs) infected with different M. scrofulaceum strains including ATCC type strains and two clinically isolated strains (rough and smooth types). All three strains resulted in the production of proinflammatory cytokines in BMDMs mediated through toll-like receptor-2 and the adaptor MyD88. Activation of MAPKs (extracellular signal-regulated kinase 1/2, and p38, and c-Jun N-terminal kinase) and nuclear receptor (NF)-${\kappa}B$ together with intracellular reactive oxygen species generation were required for the expression of proinflammatory cytokines in BMDMs. In addition, the rough morphotypes of M. scrofulaceum clinical strains induced higher levels of proinflammatory cytokines, MAPK and NF-${\kappa}B$ activation, and ROS production than other strains. When mice were infected with different M. scrofulaceum strains, those infected with the rough strain showed the greatest hepatosplenomegaly, granulomatous lesions, and immune cell infiltration in the lungs. Notably, the bacterial load was higher in mice infected with rough colonies than in mice infected with ATCC or smooth strains. Collectively, these data indicate that rough M. scrofulaceum induces higher inflammatory responses and virulence than ATCC or smooth strains.

• Molecules and Cells
• /
• v.23 no.1
• /
• pp.1-10
• /
• 2007

Invading pathogens are recognized by diverse germline-encoded pattern-recognition receptors (PRRs) which are distributed in three different cellular compartments: extracellular, membrane, and cytoplasmic. In mammals, the major extracellular PRRs such as complements may first encounter the invading pathogens and opsonize them for clearance by phagocytosis which is mediated by membrane-associated phagocytic receptors including complement receptors. The major membrane-associated PRRs, Toll-like receptors, recognize diverse pathogens and generate inflammatory signals to coordinate innate immune responses and shape adaptive immune responses. Furthemore, certain membrane-associated PRRs such as Dectin-1 can mediate phagocytosis and also induce inflammatory response. When these more forefront detection systems are avoided by the pathogens, cytoplasmic PRRs may play major roles. Cytoplasmic caspase-recruiting domain (CARD) helicases such as retinoic acid-inducible protein I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), mediate antiviral immunity by inducing the production of type I interferons. Certain members of nucleotide-binding oligomerization domain (NOD)-like receptors such as NALP3 present in the cytosol form inflammasomes to induce inflammatory responses upon ligand recognition. Thus, diverse families of PRRs coordinately mediate immune responses against diverse types of pathogens.

• Molecules and Cells
• /
• v.27 no.2
• /
• pp.211-215
• /
• 2009

Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B ($NF-{\kappa}B$). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of $NF-{\kappa}B$ activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.

• BMB Reports
• /
• v.49 no.6
• /
• pp.305-310
• /
• 2016

Toll-like receptors (TLRs) play a critical role in the innate immune response against pathogens. Each TLR recognizes specific pathogen-associated molecular patterns, after which they activate the adaptor protein MyD88 or TRIF-assembled signaling complex to produce immune mediators, including inflammatory cytokines and type I IFNs. Although the activation of TLR is important for host defense, its uncontrolled activation can damage the host. During the past decade, numerous studies have demonstrated that GSK3β is a key regulator of inflammatory cytokine production in MyD88-mediated TLR signaling via TLR2 and TLR4. Recently, GSK3β has also been implicated in the TRIF-dependent signaling pathway via TLR3. In this review, we describe current advances on the regulatory role of GSK3β in immune responses associated with various TLRs. A better understanding of the role of GSK3β in TLR signaling might lead to more effective anti-inflammatory interventions.