Neutrophil S100A9 supports M2 macrophage niche formation in granulomas

慢性炎症「肉芽腫」における好中球の新しい炎症制御系の解明 --M2マクロファージの新たな誘導メカニズム解明--. 京都大学プレスリリース. 2023-02-17.In search of inflammatory Achilles heel. 京都大学プレスリリース. 2023-03-10.Mycobacterium infection gives rise to granulomas predominantly composed of inflammatory M1-like macrophages, with bacteria-permissive M2 macrophages also detected in deep granulomas. Our histological analysis of Mycobacterium bovis bacillus Calmette-Guerin-elicited granulomas in guinea pigs revealed that S100A9-expressing neutrophils bordered a unique M2 niche within the inner circle of concentrically multilayered granulomas. We evaluated the effect of S100A9 on macrophage M2 polarization based on guinea pig studies. S100A9-deficient mouse neutrophils abrogated M2 polarization, which was critically dependent on COX-2 signaling in neutrophils. Mechanistic evidence suggested that nuclear S100A9 interacts with C/EBPβ, which cooperatively activates the Cox-2 promoter and amplifies prostaglandin E2 production, followed by M2 polarization in proximal macrophages. Because the M2 populations in guinea pig granulomas were abolished via treatment with celecoxib, a selective COX-2 inhibitor, we propose the S100A9/Cox-2 axis as a major pathway driving M2 niche formation in granulomas

Deconstructing the traditional Japanese medicine “Kampo”: compounds, metabolites and pharmacological profile of maoto, a remedy for flu-like symptoms

Pharmacological activities of the traditional Japanese herbal medicine (Kampo) are putatively mediated by complex interactions between multiple herbal compounds and host factors, which are difficult to characterize via the reductive approach of purifying major bioactive compounds and elucidating their mechanisms by conventional pharmacology. Here, we performed comprehensive compound, pharmacological and metabolomic analyses of maoto, a pharmaceutical-grade Kampo prescribed for flu-like symptoms, in normal and polyI:C-injected rats, the latter suffering from acute inflammation via Toll-like receptor 3 activation. In total, 352 chemical composition-determined compounds (CCDs) were detected in maoto extract by mass spectrometric analysis. After maoto treatment, 113 CCDs were newly detected in rat plasma. Of these CCDs, 19 were present in maoto extract, while 94 were presumed to be metabolites generated from maoto compounds or endogenous substances such as phospholipids. At the phenotypic level, maoto ameliorated the polyI:C-induced decrease in locomotor activity and body weight; however, body weight was not affected by individual maoto components in isolation. In accordance with symptom relief, maoto suppressed TNF-α and IL-1β, increased IL-10, and altered endogenous metabolites related to sympathetic activation and energy expenditure. Furthermore, maoto decreased inflammatory prostaglandins and leukotrienes, and increased anti-inflammatory eicosapentaenoic acid and hydroxyl-eicosapentaenoic acids, suggesting that it has differential effects on eicosanoid metabolic pathways involving cyclooxygenases, lipoxygenases and cytochrome P450s. Collectively, these data indicate that extensive profiling of compounds, metabolites and pharmacological phenotypes is essential for elucidating the mechanisms of herbal medicines, whose vast array of constituents induce a wide range of changes in xenobiotic and endogenous metabolism

Memory Immune Responses against Pandemic (H1N1) 2009 Influenza Virus Induced by a Whole Particle Vaccine in Cynomolgus Monkeys Carrying Mafa-A1*052∶02

We made an H1N1 vaccine candidate from a virus library consisting of 144 ( = 16 HA×9 NA) non-pathogenic influenza A viruses and examined its protective effects against a pandemic (2009) H1N1 strain using immunologically naïve cynomolgus macaques to exclude preexisting immunity and to employ a preclinical study since preexisting immunity in humans previously vaccinated or infected with influenza virus might make comparison of vaccine efficacy difficult. Furthermore, macaques carrying a major histocompatibility complex class I molecule, Mafa-A1*052∶02, were used to analyze peptide-specific CD8+ T cell responses. Sera of macaques immunized with an inactivated whole particle formulation without addition of an adjuvant showed higher neutralization titers against the vaccine strain A/Hokkaido/2/1981 (H1N1) than did sera of macaques immunized with a split formulation. Neutralization activities against the pandemic strain A/Narita/1/2009 (H1N1) in sera of macaques immunized twice with the split vaccine reached levels similar to those in sera of macaques immunized once with the whole particle vaccine. After inoculation with the pandemic virus, the virus was detected in nasal samples of unvaccinated macaques for 6 days after infection and for 2.67 days and 5.33 days on average in macaques vaccinated with the whole particle vaccine and the split vaccine, respectively. After the challenge infection, recall neutralizing antibody responses against the pandemic virus and CD8+ T cell responses specific for nucleoprotein peptide NP262-270 bound to Mafa-A1*052∶02 in macaques vaccinated with the whole particle vaccine were observed more promptly or more vigorously than those in macaques vaccinated with the split vaccine. These findings demonstrated that the vaccine derived from our virus library was effective for pandemic virus infection in macaques and that the whole particle vaccine conferred more effective memory and broader cross-reactive immune responses to macaques against pandemic influenza virus infection than did the split vaccine

Extraperitoneal Fluid Collection due to Chronic Pancreatitis

A 39-year-old man was referred to our hospital for the investigation of abdominal fluid collection. He was pointed out to have alcoholic chronic pancreatitis. Laboratory data showed inflammation and slightly elevated serum direct bilirubin and amylase. An abdominal computed tomography demonstrated huge fluid collection, multiple pancreatic pseudocysts and pancreatic calcification. The fluid showed a high level of amylase at 4,490 IU/l. Under the diagnosis of pancreatic ascites, endoscopic pancreatic stent insertion was attempted but was unsuccessful, so surgical treatment (Frey procedure and cystojejunostomy) was performed. During the operation, a huge amount of fluid containing bile acid (amylase at 1,474 IU/l and bilirubin at 13.5 mg/dl) was found to exist in the extraperitoneal space (over the peritoneum), but no ascites was found. His postoperative course was uneventful and he shows no recurrence of the fluid. Pancreatic ascites is thought to result from the disruption of the main pancreatic duct, the rupture of a pancreatic pseudocyst, or possibly leakage from an unknown site. In our extremely rare case, the pancreatic pseudocyst penetrated into the hepatoduodenal ligament with communication to the common bile duct, and the fluid flowed into the round ligament of the liver and next into the extraperitoneal space