Jin Boquan

Vα24-Invariant NKT Cells from Patients with Allergic Asthma Express CCR9 at High Frequency and Induce Th2 Bias of CD3+ T Cells upon CD226 Engagement

We have demonstrated that Vα24+Vβ11+ invariant (Vα24+i) NKT cells from patients with allergic asthma express CCR9 at high frequency. CCR9 ligand CCL25 induces chemotaxis of asthmatic Vα24+i NKT cells but not the normal cells. A large number of CCR9-positive Vα24+i NKT cells are found in asthmatic bronchi mucosa, where high levels of Th2 cytokines are detected. Asthmatic Vα24+i NKT cells, themselves Th1 biased, induce CD3+ T cells into an expression of Th2 cytokines (IL-4 and IL-13) in cell-cell contact manner in vitro. CD226 are overexpressed on asthmatic Vα24+i NKT cells. CCL25/CCR9 ligation causes directly phosphorylation of CD226, indicating that CCL25/CCR9 signals can cross-talk with CD226 signals to activate Vα24+i NKT cells. Prestimulation with immobilized CD226 mAb does not change ability of asthmatic Vα24+i NKT cells to induce Th2-cytokine production, whereas soluble CD226 mAb or short hairpin RNA of CD226 inhibits Vα24+i NKT cells to induce Th2-cytokine production by CD3+ T cells, indicating that CD226 engagement is necessary for Vα24+i NKT cells to induce Th2 bias of CD3+ T cells. Our results are providing with direct evidence that aberration of CCR9 expression on asthmatic Vα24+i NKT cells. CCL25 is first time shown promoting the recruitment of CCR9-expressing Vα24+i NKT cells into the lung to promote other T cells to produce Th2 cytokines to establish and develop allergic asthma. Our findings provide evidence that abnormal asthmatic Vα24+i NKT cells induce systemically and locally a Th2 bias in T cells that is at least partially critical for the pathogenesis of allergic asthma.

Different Neurotropic Pathogens Elicit Neurotoxic CCR9- or Neurosupportive CXCR3-Expressing Microglia

What mechanism that determines microglia accomplishing destructive or constructive role in CNS remains nebulous. We report here that intracranial priming and rechallenging with Toxoplasma gondii in mice elicit neurotoxic CCR9+Irg1+ (immunoresponsive gene 1) microglia, which render resistance to apoptosis and produce a high level of TNF-α; priming and rechallenging with lymphocytic choriomeningitis virus elicit neurosupportive CXCR3+Irg1− microglia, which are sensitive to apoptosis and produce a high level of IL-10 and TGF-β. Administration of CCR9 and/or Irg1 small interfering RNA alters the frequency and functional profiles of neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1− microglia in vivo. Moreover, by using a series of different neurotropic pathogens, including intracellular parasites, chronic virus, bacteria, toxic substances, and CNS injury to intracranially prime and subsequent rechallenge mice, the bi-directional elicitation of microglia has been confirmed as neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1− cells in these mouse models. These data suggest that there exist two different types of microglia, providing with a novel insight into microglial involvement in neurodegenerative and neuroinflammatory pathogenesis such as Alzheimer’s disease and AIDS dementia.

Expression of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) on osteoclasts and its potential role in rheumatoid arthritis.

OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 is an inhibitory receptor primarily expressed by immune cells. This study was undertaken to define the role of this molecule in osteoclast differentiation and rheumatoid arthritis. METHODS: In vitro osteoclast assays were performed to characterize the role of Leukocyte-associated immunoglobulin-like receptor-1 in murine and human osteoclastogenesis. Human Leukocyte-associated immunoglobulin-like receptor-1 expression was assessed by immunohistochemistry staining in the synovium of patients with rheumatoid arthritis. The levels of soluble Human Leukocyte-associated immunoglobulin-like receptor-1 were determined by enzyme-linked immunosorbent assay. RESULTS: We found that multinucleated osteoclast formation from mouse bone marrow cells was inhibited by treatment with a monoclonal antibody against mouse Leukocyte-associated immunoglobulin-like receptor-1 in vitro. By immunohistochemistry, we found that Leukocyte-associated immunoglobulin-like receptor-1 was mainly expressed by macrophages in the inflamed synovial tissue of rheumatoid arthritis patients. In addition, serum and synovial fluid levels of soluble Leukocyte-associated immunoglobulin-like receptor-1 were higher in rheumatoid arthritis patients compared to healthy controls or osteoarthritis patients. Moreover, overexpression of Leukocyte-associated immunoglobulin-like receptor-1 in CD14+ monocytes from healthy volunteers also inhibited human osteoclastogenesis. CONCLUSION: Collectively, these data demonstrate for the first time that Leukocyte-associated immunoglobulin-like receptor-1 inhibits osteoclastogenesis. Therefore, these results may have therapeutic implications for the treatment of rheumatoid arthritis.

Metalloprotease inhibitors reducing the shedding of human TRAIL

The expression of TNF super family member often undergoes post-translation modifying, including internalization and shedding by specific enzymes. Matrix metalloproteases (MMPs) and proteases containing a disintegrin and a metalloprotease domain (ADAMs) are often responsible for the shedding of these members. But the proteases shedding TNF-related apoptosis inducing ligand (TRAIL, a newly described TNFSF member is still indefinite. Stimulated by IFN-α2a, colon tumor cells colo205 secreted soluble TRAIL (sTRAIL), but the membrane-bound TRAIL (mTRAIL) is not up-regulated accordingly. We found metalloprotease inhibitor 1, 10-phenanthroline and TAPI-1 up-regulted mTRAIL on colo205 cells. The secretion of sTRAIL from colo205 cells stimulated by IFN-α2a was reduced significantly by them also. Endogenous sTRAIL have cytotoxic activity on raji cells, and TAPI-1 reduced cell lysis effect of the supernatant by blocking the shedding of mTRAIL into sTRAIL. In conclusion, metalloprotease inhibitors reducing the shedding of TRAIL.