Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation

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.

Which comes first: the antigen or the adjuvant?

“…In fact, Sui et al demonstrated a correlation between the set-point viral load and the peripheral expansion of a myeloid cell population that phenotypically resembled myeloid-derived suppressor cells (MDSCs), suggesting an innate dampening of the vaccine-elicited responses following viral challenge (11). This finding raises two important points to consider in future vaccine strategies for HIV-1 and other patho- The results from the study by Sui and colleagues (11) extend previous observations that TLR ligands may expand MDSCs in vivo (12)(13)(14)(15)(16). Additionally, the results from Sui et al (11) emphasize that adjuvant-driven MDSC expansion may have a detrimental impact on vaccine-induced immune responses and highlight the need for additional investigation on the impact of vaccine adjuvants on both innate and adaptive immune responses, including regulatory responses.…”

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

“…The latter are a heterogeneous population of myeloid cells with immunoregulatory functions in the context of sepsis, cancer, and trauma. 39,40 Of note, MDSC differentiation is in part regulated by Irf8 41 and may be sensitive to the EPCR ligand aPC. 42 It is currently unknown whether the EPCR-expressing Gr1CD11b POS subset exerts similar, likely stage-and context-specific immunoregulatory functions as MDSC.…”

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia

“…These cells are known to clear dying and dead cells (29). Thus, it is likely that the resolution of inflammation could be accelerated in this model.…”

“…Recently, these cells have also been described as myeloid-derived suppressor cells (MDSCs), which function to restrict ongoing inflammation and favor resolution (28,29). At 12 h postinfection, the number of cells of this type, which favor resolution, was significantly higher in the lungs of GRK5 KO mice than in those of WT mice (Fig.…”