Abstract
Ligand-mediated activation of toll-like receptors (TLRs) not only induces inflammation but also immune suppression, which is an emerging area of investigation. Multiple negative feedback intracellular mechanisms have been described that are brought into play to prevent uncontrolled TLR activation. However, the identification of TLR-induced regulatory myeloid cells is a relatively recent development that has ramifications in pathogen-induced disease state as well as in cancer. Our efforts to understand how a high dose of lipopolysaccharide (LPS), a ligand of TLR4, suppresses allergic airway inflammation led to the identification of myeloid cells that are CD11b+Griint(Ly6Gint)F4/80+ and are phenotypically and morphologically similar to myeloid-derived suppressor cells (MDSCs) which are best studied in the context of cancer. MDSCs have been also detected during infection by various bacteria, parasites and viruses, which can engage different TLRs. These TLR-induced myeloid cells produce different types of mediators to influence immune response and inflammation that can be either beneficial or detrimental to the host. One beneficial function of TLR4/MyD88-triggered MDSCs in the lung is to efferocytose apoptotic neutrophils to help resolve inflammation elicited during bacterial pneumonia. A better understanding of the generation and function of these regulatory cells would be helpful to harness their potential or suppress their function for disease-specific immune regulation.
Highlights
Our efforts to understand how a high dose of lipopolysaccharide (LPS), a ligand of TLR4, suppresses allergic airway inflammation led to the identification of myeloid cells that are CD11b+Griint(Ly6Gint)F4/80+ and are phenotypically and morphologically similar to myeloid-derived suppressor cells (MDSCs) which are best studied in the context of cancer
While our study shows a beneficial effect of MDSCs in mediating resolution of inflammation during bacterial pneumonia, in the case of infection by influenza virus, MDSC effector function needs to be regulated by iNKT cells in the absence of which immune suppression exercised by MDSCs causes increased viral titer and mortality (De Santo et al, 2008)
CONCLUDING REMARKS toll-like receptors (TLRs) signaling elicited by pathogens or by components of pathogens in concert with signals imparted by growth factors such as GM-CSF and IFN-γ has the potential to induce MDSCs in different organs including the lung
Summary
MDSCs have been detected during infection by various bacteria, parasites and viruses, which can engage different TLRs. These TLR-induced myeloid cells produce different types of mediators to influence immune response and inflammation that can be either beneficial or detrimental to the host. We will discuss the characteristics of MDSCs induced by TLR agonists such as LPS and by pathogens and the emerging field of MDSC-mediated suppression of immune responses.
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