Cooperative interactions between neurotrophin receptors and CXCR4 regulate macrophage phenotype and susceptibility to activation by HIV.

Neural damage due to inflammatory activation of macrophages and microglia is a consequence of HIV infection that leads to cognitive dysfunction. The damage is due, in part, to the release of factors that impair neuronal function but the mechanisms that control their release are poorly understood. Previous studies have shown that mature nerve growth factor (NGF) binding to tropomyosin receptor kinase A (TrkA), and proNGF acting through the p75 neurotrophin receptor (p75NTR) differentially control the phenotype of macrophages in response to HIV. However, the mechanisms responsible for these actions are unclear. The current studies demonstrated that in human monocyte-derived macrophages, CCR5 tropic HIV virions interact with the CXCR4 receptor to promote a neurotoxic macrophage phenotype. TrkA cooperatively interacted with CXCR4 to promote quick and dynamic changes in CXCR4 phosphorylation and more stable downstream actin remodeling in the form of membrane ruffles. TrkA signaling also promoted increased moacrophage calcium spiking, and low neurotoxic activity. Disruption of these interactions by HIV led to an alternative podosome-bearing phenotype with minimal calcium signaling and enhanced toxicity. Neurotrophin receptors provide an independent yet cooperative pathway for modifying the actin cytoskeleton in response to chemokines and subsequent degenerative activity. The strong opposing effects of mature and proneurotrophins may provide the opportunity to develop novel therapies that regulate the phenotype of macrophages in the context of HIV infection and perhaps other degenerative diseases.

Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice.

The persistence of HIV in the central nervous system leads to cognitive deficits in up to 50% of people living with HIV even with systemic suppression by antiretroviral treatment. The interaction of chronic inflammation with age-associated degeneration places these individuals at increased risk of accelerated aging and other neurodegenerative diseases and no treatments are available that effectively halt these processes. The adverse effects of aging and inflammation may be mediated, in part, by an increase in the expression of the p75 neurotrophin receptor (p75NTR) which shifts the balance of neurotrophin signaling toward less protective pathways. To determine if modulation of p75NTR could modify the disease process, we treated HIV gp120 transgenic mice with a small molecule ligand designed to engage p75NTR and downregulate degenerative signaling. Daily treatment with 50 mg/kg LM11A-31 for 4 months suppressed age- and genotype-dependent activation of microglia, increased microtubule associated protein-2 (MAP-2), reduced dendritic varicosities and slowed the loss of parvalbumin immunoreactive neurons in the hippocampus. An age related accumulation of microtubule associated protein Tau was identified in the hippocampus in extracellular clusters that co-expressed p75NTR suggesting a link between Tau and p75NTR. Although the significance of the relationship between p75NTR and Tau is unclear, a decrease in Tau-1 immunoreactivity as gp120 mice entered old age (>16 months) suggests that the Tau may transition to more pathological modifications; a process blocked by LM11A-31. Overall, the effects of LM11A-31 are consistent with strong neuroprotective and anti-inflammatory actions that have significant therapeutic potential.

The Understated Malignancy Potential of Nonoperative Acute Appendicitis.

Cancer of the appendix is rare and is most commonly found incidentally on pathology after an appendectomy for uncomplicated appendicitis (UA). The medical management alternative with antibiotics and observation remains an ongoing debate. The purpose of our study was to develop modern epidemiological data for adult patients completing an appendectomy for UA secondary to an appendiceal neoplasm (AN). ACS-NSQIP database was queried (2005-2016) to identify patients completing an appendectomy. Cohorts of patients who were diagnosed with UA and an AN were included in the study. Relevant perioperative clinical and outcomes data were collected. Type of AN, surgical procedure, and mortality were analyzed. A total of 239,615 UA patients were identified, of whom 2,773 (1.2%) met the inclusion criteria of AN. Patients with AN were predominantly white (79.5%), with a mean age of 54.5 ± 15.9 years, and 54.6 per cent were females. AN pathology findings included malignant neoplasm (64.5%), malignant carcinoid (17.3%), benign carcinoid (9.3%), and benign neoplasm (8.8%). The overall reported incidence was 1.2 per cent and the mortality rate was 0.7 per cent. Our study emphasizes surgical intervention in adult UA maintains a 1 per cent incidence of AN, and treatment with antibiotics alone will presumably lead to a delay in surgical treatment and progression of disease.

Differential regulation of macrophage phenotype by mature and pro-nerve growth factor.

To characterize the role of neurotrophin receptors on macrophages, we investigated the ability of nerve growth factor (NGF) and its precursor, proNGF, to regulate human macrophage phenotype. The p75 neurotrophin receptor (p75(NTR)) and TrkA were concentrated within overlapping domains on membrane ruffles. NGF stimulation of macrophages increased membrane ruffling, calcium spiking, phagocytosis and growth factor secretion. In contrast, proNGF induced podosome formation, increased migration, suppressed calcium spikes and increased neurotoxin secretion. These results demonstrate opposing roles of NGF and proNGF in macrophage regulation providing new avenues for pharmacological intervention during neuroinflammation.