Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation.

Semaphorin 3E (Sema3E) is a secreted protein that was initially discovered as a neuronal guidance cue. Recent evidence showed that Sema3E plays an essential role in regulating the activities of various immune cells. However, the exact role of Sema3E in macrophage function, particularly during inflammation, is not fully understood. We studied the impact of Sema3E gene deletion on macrophage function during the LPS-induced acute inflammatory response. We found that Sema3E-deficient (Sema3e-/- ) mice were better protected from LPS-induced acute inflammation as exemplified by their superior clinical score and effective temperature control compared with their wild-type littermates. This superior control of inflammatory response in Sema3e-/- mice was associated with significantly lower phosphorylation of ERK1/2, AKT, STAT3, and NF-κB, and a concomitant reduction in inducible NO synthase expression and production of TNF and IL-6 compared with their Sema3e+/+ littermates. Sema3e-/- mice also contained significantly higher numbers of activated macrophages compared with their Sema3e+/+ littermates at both baselines and after LPS challenge. In vivo-specific deletion of the Sema3E high-affinity receptor, plexinD1, on macrophages led to the improvement in clinical disease following exposure to a lethal dose of LPS. Collectively, our data show that Sema3E plays an essential role in dampening the early inflammatory response to LPS by regulating macrophage function, suggesting an essential role of this pathway in macrophage inflammatory response.

Semaphorin 3E Deficiency Exacerbates Airway Inflammation, Hyperresponsiveness, and Remodeling in a Mouse Model of Allergic Asthma.

Semaphorin 3E (Sema3E) plays a crucial role in axon guidance, vascular patterning, and immune regulation. Nevertheless, the role of Sema3E in asthma is still elusive. In this study, we show that genetic ablation of Sema3E in mice results in increased lung granulocytosis, airway hyperresponsiveness, mucus overproduction, collagen deposition, and Th2/Th17 inflammation. Transfer of Sema3e-/- bone marrow progenitor cells to irradiated wild-type (WT) recipients exacerbates airway hyperresponsiveness and inflammation, whereas transfer of WT bone marrow progenitor cells ameliorates asthma pathology in Sema3e-/- recipients. Sema3e-/- mice display a higher frequency of CD11b+ pulmonary dendritic cells than their WT controls at the baseline and after sensitization with house dust mite. Adoptive transfer of CD11b+ pulmonary dendritic cells from Sema3e-/- mice into WT recipients increases house dust mite-induced Th2/Th17 inflammation in the airway. Together, these findings identify Sema3E as a novel regulatory molecule in allergic asthma that acts upstream of proallergic events and suggest that targeting this molecule could be a novel approach to treat allergic asthma.

Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo.

Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not well understood. This study examines the possible role of a secreted chemorepellent, Semaphorin 3E (Sema3E), in neutrophil migration. In this study, we demonstrated that human neutrophils constitutively express Sema3E high-affinity receptor, PlexinD1. Sema3E displayed a potent ability to inhibit CXCL8/IL-8-induced neutrophil migration as determined using a microfluidic device coupled to real-time microscopy and a transwell system in vitro. The antimigratory effect of Sema3E on human neutrophil migration was associated with suppression of CXCL8/IL-8-mediated Ras-related C3 botulinum toxin substrate 1 GTPase activity and actin polymerization. We further addressed the regulatory role of Sema3E in the regulation of neutrophil migration in vivo. Allergen airway exposure induced higher neutrophil recruitment into the lungs of Sema3e-/- mice compared with wild-type controls. Administration of exogenous recombinant Sema3E markedly reduced allergen-induced neutrophil recruitment into the lungs, which was associated with alleviation of allergic airway inflammation and improvement of lung function. Our data suggest that Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation.

Association of serum beta hCG levels in women with palpable malignant breast lesions.

This study aims to determine whether serum Beta hCG can be used as a tumour marker in Breast malignancies. The objective of this study is to evaluate the serum Beta hCG in various stages of breast carcinoma and to correlate its level with disease severity and prognosis. Cross sectional analytical study of assessing serum Beta hCG in 200 patients with palpable breast malignancies at hospitals in urban Mangalore, India. In our study there was No increase in serum Beta hCG, in women with breast malignancies, but there was a pattern amongst the negative results. A Beta hCG of < 5mIU/mL is taken as negative, but in our study of 200 individuals, a mean value of 2mIU/mL was used as differentiation between low and high risk individuals. With our study we tried to correlate the value of Beta hCG with malignant breast lesions, and even though women with such lesions did not have a value of > 5mIU/mL, we found substantial evidence that women who had a value of > 2mIU/mL had a more advanced disease, be it in terms of staging, and comparing it with markers like ki67. A direct correlation between Beta hCG and severity of the disease in terms of staging was proved, hereby directly affecting the outcome of patients. Higher the level of Beta hCG, graver the prognosis. Even though Beta hCG cannot be used as tumour marker, it can be used to prognosticate the severity in women with palpable breast malignancies.

PTX3 Deficiency Promotes Enhanced Accumulation and Function of CD11c+CD11b+ DCs in a Murine Model of Allergic Inflammation.

PTX3 is a unique member of the long pentraxins family and plays an indispensable role in regulating the immune system. We previously showed that PTX3 deletion aggravates allergic inflammation via a Th17 -dominant phenotype and enhanced CD4 T cell survival using a murine model of ovalbumin (OVA) induced allergic inflammation. In this study, we identified that upon OVA exposure, increased infiltration of CD11c+CD11b+ dendritic cells (DCs) was observed in the lungs of PTX3-/- mice compared to wild type littermate. Further analysis showed that a short-term OVA exposure led to an increased number of bone marrow common myeloid progenitors (CMP) population concomitantly with increased Ly6Chigh CCR2high monocytes and CD11c+CD11b+ DCs in the lungs. Also, pulmonary CD11c+CD11b+ DCs from OVA-exposed PTX3-/- mice exhibited enhanced expression of maturation markers, chemokines receptors CCR2, and increased OVA uptake and processing compared to wild type controls. Taken together, our data suggest that PTX3 deficiency heightened lung CD11c+CD11b+DC numbers and function, hence exacerbating airway inflammatory response.

A Comparative Study of RIPASA Score and ALVARADO Score in the Diagnosis of Acute Appendicitis.

BACKGROUND: Acute appendicitis is one of the most common surgical emergencies. Different techniques have been devised to assist in equivocal cases in attempts to decrease negative appendicectomy rates. A number of scoring systems have been used for aiding in early diagnosis of acute appendicitis and its prompt management of which Alvarado score is the most popular. The accuracy of Alvarado score in the diagnosis of acute appendicitis is disappointingly low in Asian population and RIPASA scoring has been designed for the diagnosis of acute appendicitis in the Asian population. So we prospectively applied and compared Alvarado and RIPASA score in the diagnosis of acute appendicitis in Indian population. MATERIALS AND METHODS: We compared prospectively RIPASA and Alvarado scoring system by applying them to 206 patients. Both scores were calculated for patients who presented with right iliac fossa pain during the study period. Depending on clinical judgment appendicectomy was done. Post operative histopathology report was correlated with the scores. A score of 7.5 is the optimal cut off threshold for RIPASA and 7 for Alvarado scoring system. Sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) for RIPASA & Alvarado system was done. RESULTS: The sensitivity and specificity of RIPASA score were 96.2% and 90.5% respectively. The sensitivity and specificity of Alvarado score were 58.9% and 85.7% respectively. RIPASA score correctly classified 96 percent of all patients confirmed with histological acute appendicitis to the high probability group (RIPASA score greater than 7.5) compared with 58.9% with Alvarado score (Alvarado score greater than 7.0; p-value less than 0.001). CONCLUSION: RIPASA scoring system is more convenient, accurate, and specific scoring system for Indian population than Alvarado scoring system.