Iain P. Fraser

Pneumocystis carinii enhances soluble mannose receptor production by macrophages.

Phagocytosis of extracellular organisms in the alveolar spaces of the lungs represents the first-line of host defense against pulmonary pathogens. Disruption of this process is likely to interfere with the generation of appropriate specific immune responses, and lead to a delayed or inefficient clearance of the pathogen. Pneumocystis carinii, an opportunistic pathogen in immunodeficient individuals, is cleared from the lung by alveolar macrophages. In the absence of specific anti-Pneumocystis antibodies, phagocytosis is dependent on the non-opsonic macrophage mannose receptor (MR). Recent studies have demonstrated that alveolar macrophage MR activity is downregulated in individuals infected with HIV, and that functional MR is shed from the macrophage cell surface. Here we report that P. carinii enhances the formation of soluble MR by macrophages in vitro. Soluble MR was detected in cell-free alveolar fluid from humans infected with HIV and/or P. carinii, but not in alveolar fluid from healthy controls. Soluble MR was found in association with extracellular clumps of P. carinii in the lungs of mice with P. carinii pneumonia, and was associated with P. carinii organisms purified from these mice. When purified P. carinii organisms were incubated with soluble MR-containing supernatants, they were phagocytosed less readily by alveolar macrophages than were control organisms. Our results suggest that P. carinii organisms enhance the shedding of MR from the surface of alveolar macrophages, and that the resultant soluble MR binds to intra-alveolar organisms, thereby interfering with their non-opsonic uptake via the macrophage cell surface MR.

TLR-independent pattern recognition receptors and anti-inflammatory mechanisms

Pattern recognition receptors recognize molecular patterns associated with the surfaces of microbes and apoptotic cells. These receptors act alone and in concert to bind, phagocytose, and transduce cellular signals derived from these molecular patterns. The outcome of these interactions is dependent on the nature of the ligands, and upon the nature and combination of the ligated receptors. Whereas much attention has been focused on the properties and activities of the Toll-like receptors (TLRs) in this process, many other pattern recognition molecules have been described. Here we review some of these non-TLR receptors and their ligands, and focus attention on the mannose binding lectin, a humoral pattern recognition molecule. In addition, we describe how recognition of apopotic cells via pattern recognition receptors appears to result in responses that differ from those elicited by microbial ligands.

The Mannose-Binding Lectin: An Infection Susceptibility Gene

A critical but unanswered question is what defines each individual’s pre-morbid susceptibility to infection? w e propose that individuals must have an “immune haplotype” that shapes their response to infectious agents. Infection is a balance between the intrinsic virulence of the infectious agent and the host defenses. Recent viral outbreaks of SARS and influenza serve to illustrate this point as these viruses cause severe disease in certain individuals, yet there are others in whom the same infectious challenge results in minimal symptoms. On the other hand it might be that those self same people who are resistance to one particular viral infection might be susceptible to other infection challenges. Similar rules can apply to susceptibility to bacterial infections.

Mannose receptor and phagocytosis

Publisher Summary This chapter discusses the role of mannose receptor in phagocytosis. The mannose receptor (MR) is a ≈175 kDa transmembrane receptor expressed on resident macrophage subpopulations, dendritic cells, and on subsets of endothelial cells. The mannose receptor mediates the uptake of ligands bearing appropriately configured carbohydrate residues. Its ligand binding profile confers on it a broad capacity to recognize non-self over self-molecules, in keeping with its designation as a pattern recognition receptor. Ligation of the receptor is followed by internalization of the bound ligand, and is coupled to a variety of cellular processes directed toward destruction of pathogens, participation in the inflammatory response, or stimulation of the immune system. While this receptor is capable of both endocytic and phagocytic uptake, the signaling pathways utilized remain to be determined.

Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators

Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED50 values of 1–2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.