Cutting Edge: Critical Role of Intracellular Osteopontin in Antifungal Innate Immune Responses

Inoue, Makoto; Moriwaki, Yuji; Arikawa, Tomohiro; Chen, Yu Hsun; Oh, Young Joo; Oliver, Timothy N.; Shinohara, Mari L.

doi:10.4049/jimmunol.1002735

Cited by 49 publications

(67 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…iOPN was previously established as a proinflammatory molecule, but we found in this study that iOPN served as a negative regulator of inflammatory responses in concert with adaptive immune cells. iOPN faithfully behaves as a proinflammatory molecule when hosts are comprised of the innate immune system alone (24). However, we have shown that iOPN could behave as an anti-inflammatory molecule when the adaptive immune system is present.…”

Section: Discussionmentioning

confidence: 75%

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Inoue¹,

Arikawa²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. However, the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear. Here, we report that T cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling TNF and IL-10 levels by macrophage CD40 stimulation. The cross-talk between CD40 and toll-like receptor (TLR4) signaling first mediates IL-1 receptor-associated kinase 1 (IRAK1) nuclear translocation and its binding to the IL-10 gene promoter in macrophages, without interfering with the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA. To induce IRAK1-mediated IL-10 expression, signals from both CD40 and TLR4 are essential. CD40 signaling induces IRAK1 sumoylation in the presence of TNF receptor-associated factor 2 (TRAF2) and intracellular isoform of osteopontin (iOPN) whereas TLR4 signaling provides IFN regulatory factor 5 (IRF5) as a chaperone for sumoylated IRAK1 nuclear translocation. Interaction of T cells with macrophages was observed in the spleen in vivo after endotoxemia induction with LPS injection. Our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage CD40 in LPS endotoxemia.OPN | CD40L | CD154 | simultaneous stimulation | T cell migration

show abstract

Section: Discussionmentioning

confidence: 75%

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Inoue¹,

Arikawa²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These findings suggest that in DENinduced HCC, production of cytokines by resident liver macrophages is mainly via the TLR4/MyD88 signaling. Previous studies have suggested that iOPN might perform as one of the intracellular regulators of TLR2/TLR9 signaling to balance the cytokine milieu (16,21). In plasmacytoid dendritic cells, shortly after TLR9 engagement, iOPN interacted with MyD88 and enhanced interferon-a production (16).…”

Section: Discussionmentioning

confidence: 99%

“…In plasmacytoid dendritic cells, shortly after TLR9 engagement, iOPN interacted with MyD88 and enhanced interferon-a production (16). In antifungal innate immunity, iOPN acted as an adaptor molecule in TLR2 and dectin-1 signaling pathways and increased zymosan-induced cytokine production such as IL1b and IL10 (21). Following TLR stimulation in macrophages, iOPN was induced in vivo and in vitro and negatively regulated interferon-b production in murine macrophages (17).…”

Section: Discussionmentioning

confidence: 99%

“…In plasmacytoid dendritic cells, it interacts with myeloid differentiation primary response gene 88 (MyD88) and enhances interferon-a production through Toll-like receptor 9 (TLR9) signaling (16). In antifungal innate immunity, it participates in cluster formation of fungal receptors, as an adaptor molecule of TLR2 and dectin-1 signaling pathways, to enhance phagocytosis and clearance of fungus (21).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intracellular Osteopontin Inhibits Toll-like Receptor Signaling and Impedes Liver Carcinogenesis

Fan

Wei

et al. 2015

Cancer Research

View full text Add to dashboard Cite

Osteopontin (OPN) has been implicated widely in tumor growth and metastasis, but the range of its contributions is not yet fully understood. In this study, we show that genetic ablation of Opn in mice sensitizes them to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Opn-deficient mice (Opn À/À mice) exhibited enhanced production of proinflammatory cytokines and compensatory proliferation. Administering OPN antibody or recombinant OPN protein to wild-type or Opn À/À mice-derived macrophages, respectively, had little effect on cytokine production. In contrast, overexpression of intracellular OPN (iOPN) in Opn-deficient macrophages strongly suppressed production of proinflammatory cytokines. In addition, we found that iOPN was able to interact with the pivotal Toll-like receptor (TLR) signaling protein MyD88 in macrophages after stimulation with cellular debris, thereby disrupting TLR signaling in macrophages. Our results indicated that iOPN was capable of functioning as an endogenous negative regulator of TLR-mediated immune responses, acting to ameliorate production of proinflammatory cytokines and curtail DENinduced hepatocarcinogenesis. Together, our results expand the important role of OPN in inflammation-associated cancers and deepen its relevance for novel treatment strategies in liver cancer.Cancer Res; 75(1); 86-97. Ó2014 AACR.

show abstract

“…Other studies have shown that osteopontin, which participates in innate immune responses to other infectious agents, is highly upregulated in AMs of Pneumocystis-infected immunosuppressed rats (37). Recently, Inoue et al have shown that the intracellular isoform of osteopontin is involved as an adaptor molecule in the collaboration of Toll-like receptor 2, dectin 1, and mannose receptor following interaction of Pneumocystis with AMs (129). Additional studies demonstrated a role for intracellular osteopontin in enhancement of phagocytosis and clearance of Pneumocystis (129).…”

Section: Macrophagesmentioning

confidence: 99%

Colonization by Pneumocystis jirovecii and Its Role in Disease

2012

View full text Add to dashboard Cite

SUMMARY Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research.

show abstract

Cutting Edge: Critical Role of Intracellular Osteopontin in Antifungal Innate Immune Responses

Cited by 49 publications

References 31 publications

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Intracellular Osteopontin Inhibits Toll-like Receptor Signaling and Impedes Liver Carcinogenesis

Colonization by Pneumocystis jirovecii and Its Role in Disease

Contact Info

Product

Resources

About