OX40 Ligand Regulates Inflammation and Mortality in the Innate Immune Response to Sepsis

Abstract

The initial phase of sepsis is characterized by massive inflammatory cytokine production which contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity and recent studies describe their presence on neutrophils and monocytes, suggesting a potential role for regulating cytokine production in innate immunity. The purpose of this study is to determine the role for OX40-OX40L interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on both monocytes and neutrophils, with mortality and ICU stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was evidenced by improved survival, decreased cytokine production and a decrease in remote organ damage in OX40L −/− mice. The finding of similar results with an OX40L antibody suggests a potential future therapeutic role for OX40L blockade in sepsis. The inability of α-OX40L to provide significant protection in macrophagedepleted mice establishes macrophages as an indispensible cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of α-OX40L antibody in RAG1 −/− mice, further confirms a T-cell independent role for OX40L stimulation in sepsis. In conclusion, our data provide a novel in vivo role for OX40-OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.

The Burn Wound Inflammatory Response Is Influenced by Midazolam

“…The numerous attempts at anticytokine treatment in human and animal sepsis models have for the most part, not been very successful most likely due to the redundant effects of cytokines and immunosuppression [37]. The combination of the findings in the current work and the results of our previous investigation [8] suggest that mixed BDZs such as midazolam may be utilized to ascertain the signal transduction players that could be targeted for the rationale design of therapies which attenuate (not ablate) the proinflammatory cytokine response while enhancing other innate immune defenses following burn injury and/or sepsis.…”

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

“…Furthermore, redundancy in such late costimulators that act at the same stage as OX40/OX40L (such as 4-1BB/4-1BBL) would provide the signals required for maintenance of sufficient inflammation and the development of immunological memory (32, 34, 39, 40). Interestingly, OX40 or OX40L blockade is actually beneficial in infectious diseases associated with immunopathology, such as virally induced myocarditis (41), respiratory viruses (34), and polymicrobial sepsis (42), which are significant complications of current treatment strategies for arthritis. For these reasons, blockade of late T-cell costimulators and their receptors should be tested in humans.…”

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

“…To establish that macrophages were required for the protective effects of IL-5 in vivo, we used MaFIA mice, which allow for systemic macrophage depletion through Fas ligand-mediated apoptosis (41,42). Similar to observations with C57BL/6 mice, IL-5 protected macrophage-intact (nondepleted) MaFIA mice.…”