17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and liveE. coli

Abstract

Detection and clearance of bacterial infection require balanced effector and resolution signals to avoid chronic inflammation. Detection of GNB LPS by TLR4 on m induces inflammatory responses, contributing to chronic inflammation and tissue injury. LXs and Rvs are endogenous lipid mediators that enhance resolution of inflammation, and their actions on primary human m responses toward GNB are largely uncharacterized. Here, we report that LXA(4), LXB(4), and RvD1, tested at 0.1-1 μM, inhibited LPS-induced TNF production from primary human m, with ATL and 17(R)-RvD1, demonstrating potent inhibition at 0.1 μM. In addition, 17(R)-RvD1 inhibited LPS-induced primary human m production of IL-7, IL-12p70, GM-CSF, IL-8, CCL2, and MIP-1α without reducing that of IL-6 or IL-10. Remarkably, when stimulated with live Escherichia coli, m treated with 17(R)-RvD1 demonstrated increased TNF production and enhanced internalization and killing of the bacteria. 17(R)-RvD1-enhanced TNF, internalization, and killing were not evident for an lpxM mutant of E. coli expressing hypoacylated LPS with reduced inflammatory activity. Furthermore, 17(R)-RvD1-enhanced, E. coli-induced TNF production was evident in WT but not TLR4-deficient murine m. Thus, Rvs differentially modulate primary human m responses to E. coli in an LPS- and TLR4-dependent manner, such that this Rv could promote resolution of GNB/LPS-driven inflammation by reducing m proinflammatory responses to isolated LPS and increasing m responses important for clearance of infection.

Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy

“…sensitivity to endotoxin-driven inflammation in such patients. LX analogues effectively reduce intestinal inflammation [64], inhibit endotoxin-induced production of pro-inflammatory cytokines by primary human macrophages [65] and are currently in clinical trials as oral agents for inflammatory bowel disease in Europe. The potential of LX analogues and lipid mediator precursors AA (arachidonic acid), DHA (decosahexaenoic acid) and EPA (eicosapentaenoic acid), is reflected in ongoing clinical trials testing their safety and efficacy in a range of human diseases [66], including primary sclerosing cholangitis, colitis and toxicities associated with chemotherapy for GI tumours (http://clinicaltrials.gov).…”

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

“…SPMs, primarily lipoxins and D-series resolvins, can dampen LPS-induced inflammation in mouse models of acute lung injury. Resolvin D1 (RvD1) and other SPMs dampen proinflammatory cytokines and cellular influx to reduce LPS-induced tissue destruction and mortality in mice (19,20). SPMs have even been effective against live bacteria, promoting resolution in several models of sepsis and nontypeable Haemophilus influenzae lung infection, restoring lung physiology and reducing the need for antibiotics in infected mice (21)(22)(23).…”

Resolvin D1 Dampens Pulmonary Inflammation and Promotes Clearance of Nontypeable Haemophilus influenzae

“…First, AT-RvD1 does not broadly block all cytokine signaling, distinguishing SPMs from other strictly anti-inflammatory therapies. This non-immunosuppressive nature is further seen as SPMs increase macrophage influx, enhance efferocytosis, and increase the phagocytic abilities of macrophages (20-22, 25, 33, 39). Second, AT-RvD1 decreases in KC levels early on demonstrate that SPMs can preferentially regulate early cytokine release to jump-start resolution.…”