Sathisha Upparahalli Venkateshaiah

Pathogenic mechanisms of pancreatitis

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.

Regulatory effects of IL-15 on allergen-induced airway obstruction

Background: Airway obstruction is a physiologic feature of asthma, and IL‐15 might have an important role in asthma pathogenesis. Objective: We tested the hypothesis that regulation of IL‐15 is critical for preservation of allergen‐induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine. Methods: Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene–deficient mice and IL‐15–overexpressing mice in an allergen‐induced murine model of asthma. We assessed eosinophil numbers by using anti–major basic protein immunostaining, goblet cell hyperplasia by using periodic acid–Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA. Results: We made a novel observation that IL‐15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL‐15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen‐induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline‐inducible CC10–IL‐15 bitransgenic mice. Doxycycline‐exposed, Aspergillus species extract–challenged CC10–IL‐15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL‐4, IL‐5, and IL‐13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen‐challenged doxycycline‐exposed compared with non–doxycycline‐exposed CC10–IL‐15 bitransgenic mice. Mechanistically, we observed that IL‐15–mediated protection of airway obstruction is associated with induced IFN‐&ggr;– and IL‐10–producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL‐15 agonist (ALT‐803) improved airway resistance and compliance in an experimental asthma model. Conclusion: We report our novel finding that IL‐15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

Elements Involved In Promoting Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGID) are food allergen-induced allergic gastrointestinal disorders, characterized by accumulation of highly induced eosinophils in different segments of gastrointestinal tract along with eosinophil microabssess and extracellular eosinophilic granules in the epithelial layer. EGID are both IgE- and cell-mediated group of diseases that include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC). Despite the increased incidences and considerable progress made in understanding EGID pathogenesis. The mechanism is still not well understood. It has been shown that IL-4, IL-5, IL-13, IL-15, IL-18, eotaxin-1, eotaxin-2 and eotaxin-3 play a critical role in EGID pathogenesis. Currently, the only criterion for diagnosing EoE, EGE and EC are repetitive endoscopic and histopathological evaluation of biopsies along with other clinical characteristics/manifestations. Antigen elimination and corticosteroid therapies are the most effective therapies currently in practice for the treatment of EGID. The cytokines (anti-IL-5 and anti-IL-13) therapy trials were not very successful in case of EoE. Most recently, a clinical trial using anti-IL-13 reported only 60% reduced esophageal eosinophilia without achieving primary endpoint. This clinical finding is not surprising and is in accordance with our earlier report indicating that IL-13 is not critical in the initiation of EoE. Notably, EGID still has no reliable noninvasive diagnostic biomarkers. Hence, there is a great necessity to identify novel noninvasive diagnostic biomarkers that can easily diagnose EGID and provide an effective therapy. Now, the attention is required to target cell types like iNKT cells that produce eosinophil active cytokines and is found induced in the pathogenesis of both experimental and human EoE. iNKT cell neutralization is shown to protect allergen-induced EoE in experimental model. In this review, we have discussed the key elements that are critical in the disease initiation, progression, pathogenesis and important for future diagnostic and therapeutic interventions for EGID.

Possible Noninvasive Biomarker of Eosinophilic Esophagitis: Clinical and Experimental Evidence.

Eosinophilic esophagitis (EoE) diagnosis and follow-up response to therapy is based on repeated endoscopies and histological examination for eosinophils/HPF. The procedure is invasive and risky in particular for the pediatric population. Presently, there is no highly sensitive and specific noninvasive blood test available to monitor the disease pathogenesis. Reports indicate the expression of PDL1 (CD274) on the eosinophils in allergic patients. Herein, we report that CD274-expressing and -nonexpressing eosinophils were detected in both examined pediatric and adult EoE patients. We show that CD274 expression on blood eosinophils and blood mRNA expression levels increase in the blood of EoE patients and decrease following treatment. These observations are consistent with the esophageal eosinophilia of before and after treatment in both examined patients. These two clinical and experimental analysis reports provide the possibility that the CD274 mRNA and CD274-expressing esinophil levels may be novel possible noninvasive biomarkers for EoE.

Role of vasoactive intestinal peptide in promoting the pathogenesis of eosinophilic esophagitis (EoE)

Eosinophilic esophagitis (EoE) is associated with eosinophil and mast cell accumulation, which promotes dysphagia and esophageal dysmotility. Cytokines and chemokines implicated in eosinophil-, mast cell–, and basophil-mediated EoE pathogenesis include interleukin (IL)-5, IL-13, thymic stromal lymphopoietin, and eotaxin-3. A correlation between IL-5 and eotaxin-3 expression and eosinophil infiltration has been observed. Nevertheless, it is not clear if eotaxin-3 is the only chemokine, or one of several, that directs eosinophil accumulation in EoE. Herein, we present evidence that a neuroimmune pathway is involved in eosinophil and mast cell accumulation and degranulation in human EoE. Morphologically, eosinophils accumulate near nerves within the muscular mucosa of the esophagus (Figure 1A). This spatial association suggests that nerve cells may release

Role of eosinophils in the initiation and progression of pancreatitis pathogenesis

Eosinophilic pancreatitis (EP) is reported in humans; however, the etiology and role of eosinophils in EP pathogenesis are poorly understood and not well explored. Therefore, it is interesting to examine the role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Accordingly, we performed anti-major basic protein immunostaining, chloroacetate esterase, and Massons trichrome analyses to detect eosinophils, mast cells, and collagen in the tissue sections of mouse and human pancreas. Induced eosinophils accumulation and degranulation were observed in the tissue sections of human pancreatitis, compared with no eosinophils in the normal pancreatic tissue sections. Similarly, we observed induced tissue eosinophilia along with mast cells and acinar cells atrophy in cerulein-induced mouse model of chronic pancreatitis. Additionally, qPCR and ELISA analyses detected induced transcript and protein levels of proinflammatory and profibrotic cytokines, chemokines like IL 5, IL-18, eotaxin-1, eotaxin-2, TGF-β1, collagen-1, collagen-3, fibronectin, and α-SMA in experimental pancreatitis. Mechanistically, we show that eosinophil-deficient GATA1 and endogenous IL-5-deficient mice were protected from the induction of proinflammatory and profibrotic cytokines, chemokines, tissue eosinophilia, and mast cells in a cerulein-induced murine model of pancreatitis. These human and experimental data indicate that eosinophil accumulation and degranulation may have a critical role in promoting pancreatitis pathogenesis including fibrosis. Taken together, eosinophil tissue accumulation needs appropriate attention to understand and restrict the progression of pancreatitis pathogenesis in humans. NEW & NOTEWORTHY The present study for the first time shows that eosinophils accumulate in the pancreas and promote disease pathogenesis, including fibrosis in earlier reported cerulein-induced experimental models of pancreatitis. Importantly, we show that GATA-1 and IL-5 deficiency protects mice form the induction of eosinophil active chemokines, and profibrotic cytokines, including accumulation of tissue collagen in an experimental model of pancreatitis. Additionally, we state that cerulein-induced chronic pancreatitis is independent of blood eosinophilia.

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases.

Food-Induced Acute Pancreatitis

Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.

A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils

The current studies demonstrate a critical role of IL-18 in transforming IL-5 generated naïve eosinophils into the distinct inflammatory CD101+CD274+ expressing mature and activated tissue eosinophils that promote disease pathogenesis.

Intestinal overexpression of interleukin (IL)-15 promotes tissue eosinophilia and goblet cell hyperplasia

Interleukin (IL)‐15 overexpression in eosinophilic gastrointestinal disorders is reported, but IL‐15′s role in promoting eosinophilic gastroenteritis is largely unknown. Therefore, we generated enterocyte‐overexpressed IL‐15 transgenic mice using Fabpi promoter. The Fabpi‐IL‐15 (iIL‐15) transgenic mice showed induced IL‐15 levels in the jejunum with a marked increase in jejunum eosinophils. However, no induction of eosinophilia in the blood or any other gastrointestinal segment was observed. Eosinophilia in the jejunum villus was substantially higher in iIL‐15 mice compared to wild‐type mice. In addition, goblet cell hyperplasia was also observed in the jejunum of iIL‐15 mice. Furthermore, a significant correlation between induced IL‐15 transcript and the IL‐18 transcripts was observed. Therefore, to further understand the role of IL‐18 in IL‐15 mice associated gastrointestinal disorders, we generated iIL‐15/IL‐18Rα−/− mice. Using these mice, we found that IL‐18 has an important role in promoting IL‐15‐induced eosinophilia. As intestinal IL‐15 overexpression is reported in food intolerance, we examined OVA intolerance in iIL‐15 mice. The OVA‐sensitized and challenged iIL‐15 mice experienced weight loss, diarrhea and eosinophilia in the jejunum. Taken together, our findings demonstrate that intestinal IL‐15 overexpression induces IL‐18‐dependent eosinophilia and immunoglobulins in the intestine that promotes food allergic responses.