Theresa Pizarro - Academia.edu (original) (raw)

Papers by Theresa Pizarro

Inflammatory Bowel Diseases

Lay Summary The advent of single-cell technologies has revolutionized analyses of IBD-specific pr... more Lay Summary The advent of single-cell technologies has revolutionized analyses of IBD-specific processes by identifying important, often novel, mucosal cells subpopulations and their associated functions. We discuss recent findings reporting transcriptomic and cellular diversity of treatment-naïve and treated patients with ileal-specific CD.

ABSTRACTThe main form of COVID-19 transmission is via ‘oral-respiratory droplet contamination’ (d... more ABSTRACTThe main form of COVID-19 transmission is via ‘oral-respiratory droplet contamination’ (droplet; very small drop of liquid) produced when individuals talk, sneeze or cough. In hospitals, health-care workers wear facemasks as a minimum medical ‘droplet precaution’ to protect themselves. Due to the shortage of masks during the pandemic, priority is given to hospitals for their distribution. As a result, the availability/use of medical masks is discouraged for the public. However, given that asymptomatic individuals, not wearing masks within the public, can be highly contagious for COVID-19, prevention of ‘environmental droplet contamination’ (EnDC) from coughing/sneezing/speech is fundamental to reducing transmission. As an immediate solution to promote ‘public droplet safety’, we assessed household textiles to quantify their potential as effective environmental droplet barriers (EDBs). The synchronized implementation of a universal ‘community droplet reduction solution’ is di...

The Journal of Immunology

New evidence suggests the implication of IL-9-secreting TH9 cells in the pathogenesis of Crohn’s ... more New evidence suggests the implication of IL-9-secreting TH9 cells in the pathogenesis of Crohn’s disease (CD). The role of death receptor 3 (DR3) in the differentiation and function of TH9 cells in CD is not fully explored. Thus, here, we investigated the role of a functional DR3 receptor in disease progression and activation of downstream signaling pathways relevant to TH9 cells. We found that lack of DR3 ameliorated ileitis in SAMP/YitFc (SAMP,WT) mice, reduced by 40% Baft3, PU.1, il-9 mRNAs and IL-9 protein, increased by 3-fold Id3 mRNA in ileal tissues (P≤0.003). TH9 cells from DR3−/−×SAMP (KO) mice harbored 2-fold less il-9 mRNA and IL-9 and TNF proteins (P≤0.0002), 5-fold higher IL-10 protein than WT TH9 cells (P<0.0001). RNA-seq analysis of WT and KO TH9 cells is currently being analyzed. Rag2−/− recipients of KO TH9 cells developed less severe colitis (P=0.005). Histology score of ilea and colons from SAMP×Rag2−/− is currently being evaluated. The frequency of KO TH9 cell...

The American Journal of Pathology

Nature Reviews Gastroenterology & Hepatology, 2020

Inflammatory bowel disease (IBD), as do most chronic inflammatory disorders, displays unique feat... more Inflammatory bowel disease (IBD), as do most chronic inflammatory disorders, displays unique features and confers different risk factors in male and female patients. Importantly, sex-based differences in IBD exist for epidemiological incidence and prevalence among different age groups, with men and women developing distinct clinical symptoms and disparity in severity of disease. In addition, the presentation of comorbidities in IBD displays strong sex differences. Notably, particular issues exclusive to women’s health, including pregnancy and childbirth, require specific considerations in female patients with IBD of childbearing age that can have a substantial influence on clinical outcomes. This Review summarizes the latest findings regarding sex-based differences in the epidemiology, clinical course, comorbidities and response to current therapies in patients with IBD. Importantly, the latest basic science discoveries in this area of investigation are evaluated to provide insight into potential mechanisms underlying the influence of sex on disease pathogenesis, as well as to design more personalized and efficacious care, in patients with IBD. Inflammatory bowel disease (IBD) has different manifestations and associated risk factors between the sexes. This Review explores the sex-based differences in presentation and management of IBD, as well as insights into sex-based differences in pathogenesis and underlying mechanisms inferred from basic research. Epidemiological studies have shown a greater predominance and severity of Crohn’s disease in women than in men, but a greater predominance and severity of ulcerative colitis in men than in women. Epidemiological studies have also demonstrated that colorectal cancer is more common among men than among women with chronic ulcerative colitis with a high degree of inflammation. Female sex hormones, including oral contraceptives, influence the immune system and contribute to the exacerbation of IBD symptoms in women. Female patients with IBD who wish to become pregnant are advised to wait until clinical remission. The incidence of extraintestinal manifestations and comorbidities in patients with IBD frequently shows differences between men and women. Two experimental mouse models of Crohn’s disease (SAMP1/YitFc and Tnf ΔARE/+ strains) recapitulate female sex bias and represent promising tools for future mechanistic studies underlying sex-based differences in IBD pathogenesis.

Frontiers in Immunology, 2021

Editorial on the Research Topic Cytokines and Intestinal Mucosal Immunity Since discovery of the ... more Editorial on the Research Topic Cytokines and Intestinal Mucosal Immunity Since discovery of the prototypic cytokines, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF), almost 50 years ago (1, 2), an explosion of information has followed regarding the biology of cytokines and their critical role(s) during health and disease. To date, 41 interleukins and more than 18 TNF superfamily (TNFSF) members have been described. Notably, in 1990, our group was one of the first to show that blockade of a single cytokine, i.e., IL-1, was effective in markedly reducing the severity of experimental colitis (3), laying the foundation to conceptualize that targeting of an individual cytokine could successfully impact the development and progression of a specific disease. The role of cytokines, in fact, has been particularly important in the gastrointestinal tract, both in maintaining homeostasis and during chronic inflammatory disorders, such as inflammatory bowel disease (IBD), wherein many cell types have the ability to both react to, and produce, cytokines in response to a variety of antigenic stimuli, dietary products, microbial components, and toxic agents. This wealth of new information has led to the approval of different anti-cytokine therapies, such as anti-TNF and anti-IL-12/23 monoclonal antibodies, for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD. In addition, novel small molecule inhibitors, such as those targeting the JAK/STAT pathway, and which possess broad anti-cytokine activity, are now available in the armamentarium of gastroenterologists to treat IBD. In this Research Topic, the role of canonical, and more novel, cytokines are discussed in the context of intestinal immunity and chronic gut inflammation. Three articles focus on the role(s) of TNFSF members (Li et al.; Valatas et al.; Giles et al.). Specifically, Li et al. and Valatas et al. report the importance of the TL1A (TNF-like ligand 1A, TNFSF15)/DR3 (death receptor 3,TNFRSF25) ligand-pair, for which increasing evidence suggests a critical role not only in the pathogenesis of IBD, but also in the development of gut fibrosis/fibrostenotic disease. These papers highlight TL1A/ DR3's pleiotropic functions in regulating the balance between T effector and T regulatory cells (Tregs), as well as innate lymphoid cells (ILCs), thereby serving as a vital rheostat during IBD. Notably, monoclonal antibodies against TL1A are currently in clinical trials for the treatment of CD and UC, and will shortly reveal the efficacy of anti-TL1A/DR3 strategies in IBD.

Inflammatory Bowel Diseases, 2022

Recent studies have documented the complexity of the intestinal fungal community (‘mycobiome’) in... more Recent studies have documented the complexity of the intestinal fungal community (‘mycobiome’) in mice, and clinical and experimental observations have shown that the mycobiome influences both gut health and disease, e.g., inflammatory bowel disease (IBD). In fact, prior studies have shown that Crohn’s disease (CD) patients, compared to healthy controls, harbor higher levels of intestinal Candida tropicalis (Ct), which is the major fungal species detected in the colons of colitic mice after DSS challenge. More recently, Debaryomyces hansenii (also known as Candida famata) has been found in intestinal wounds of mice and inflamed mucosal tissues of CD patients. Moreover, proteins encoded by genes within IBD susceptibility loci, such as the pattern recognition receptor (PRR), NOD2, are known not only to recognize bacterial components, but also a fungal cell wall element, chitin. In fact, the role of PRRs in regulating immunity against intestinal fungi, and how fungi influence IBD remai...

Frontiers in Cellular and Infection Microbiology, 2022

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countr... more Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflam...

homeostatic mechanism to restrain chronic

Journal of Clinical Investigation, 2021

Digestive Diseases and Sciences, 2017

Mucosal immunology, Jan 3, 2016

Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that ... more Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of nuclear factor κB (NFκB) signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of signa...

Journal of Hepatology, 2015

inflammatory leukocytes. CX3CR1 is expressed on multiple cell types including monocytes and dendr... more inflammatory leukocytes. CX3CR1 is expressed on multiple cell types including monocytes and dendritic cells (DCs). Recent evidence indicates that CX3CR1 deficiency exacerbates liver injury and fibrosis in CCl 4 treated mice, however, the mechanisms involved are still poorly understood. We aimed at elucidating the role of CX3CR1 for hepatic DC responses in homeostasis and acute liver injury. Methods: CX3CR1 GFP/GFP and CX3CR1 +/GFP mice were injected intraperitoneally with CCl 4 (0-0.6 ml/kg) and liver mononucleated cells were analyzed by flow cytometry 36 hours later. Results: In homeostasis, CX3CR1 GFP/GFP mice showed a significant lower percentage of CD11c high /MHCII + / CX3CR1 high DCs in liver parenchyma (p < 0.05) than CX3CR1 +/GFP. Conversely, knockout mice displayed a higher percentage of liver plasmocytoid DCs B220 + CD11c + MHCII + compared to CX3CR1 +/GFP. In line with the tolerogenic activity of liver DCs, CTLA4 expression by CD4+/CD25+ regulatory T-cells (Tregs) was lower in CX3CR1 GFP/GFP mice, despite the overall number of hepatic CD4 + T cells was comparable between the two strains. Recent evidence indicates that liver injury is associated with changes in hepatic DCs. CCl 4 treatment of wild-type and CX3CR1 GFP/GFP mice lowered the pool of myeloid DCs and deeply affected the monocyte differentiation to DCs in the knockout strain. After CCl 4 treatment both CX3CR1 +/GFP and CX3CR1 GFP/GFP strains showed very strong liver recruitment of CD11c high /MHCII + CD11b + monocytederived DC (moDC). Interestingly, in CX3CR1 +/GFP mice, these CD11c + MHCII + CD11b + CX3CR1 high moDCs had higher expression of the co-stimulatory proteins CD80 and CD40, indicating CX3CR1's involvement in moDCs maturation. However, CX3CR1 deficiency also affected the expression of immune regulatory PDL-1 on DCs (p < 0.01). Accordingly, CCl 4 treated CX3CR1 GFP/GFP mice showed a higher expression of T-cell activation marker CD69 associated to a lowering in hepatic CD4 + CD25 + Foxp3 + regulatory T cells. Conclusions: These results suggest a novel role of CX3CL1/CX3CR1 axis in liver DC maturation/differentiation that may account for the increased severity of liver injury in CX3CR1-deficient mice.

The Journal of Immunology, 2003

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 I... more This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Journal of Clinical Investigation, 2004

SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, si... more SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4 + T cells expressing the α E β 7 integrin. Although α E β 7 + CD4 + T cells possess a regulatory phenotype (CD25 + , L-selectin lo , and CD45RB lo), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4 + T cells, although the CD4 + CD25 + subset, which overlaps with the α E β 7 + CD4 + subset, prevents colitis. The α E β 7 + CD4 + T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA + cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4 + T cells increases ileitis severity in SCID mice compared with transfer of CD4 + T cells alone. SAMP1/YitFc B cells prevent α E β 7 + CD4 + T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis. Nonstandard abbreviations used: follicular helper T cell (TFH cell); GITR ligand (GITRL); glucocorticoid-induced TNF receptor (GITR); inducible T cell costimulator (ICOS); inflammatory bowel disease (IBD); mesenteric lymph node (MLN); phycoerythrin (PE); regulatory T cell (Treg cell).

Cytokine, 2012

In addition to their well-known role in acute injury and chronic inflammation "innate" cytokines ... more In addition to their well-known role in acute injury and chronic inflammation "innate" cytokines play an important role in health and the maintenance of normal immune homeostasis. This group includes the prototypic cytokines IL-1 and TNF as well as several other members belonging to the IL-1 and TNF family, such as IL-18, IL-33, IL-36-38, and TL1A. The dichotomous role of these cytokines has been best characterized in the intestine where innate cytokines may play both a protective and a pro-inflammatory role, depending upon the immmunological status of the host or the type and phase of the inflammatory process. This new information has produced novel pathogenetic hypotheses that have important translational implications both in regard to the prevention and treatment of chronic intestinal inflammation, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. This review will discuss and summarize current data regarding the role of IL-1, TNFα, and their family members in regulating gut mucosal homeostasis and chronic intestinal inflammation.

International Journal of Molecular Sciences, 2020

(1) Background: Colorectal cancer (CRC) is among the best examples of the relationship between in... more (1) Background: Colorectal cancer (CRC) is among the best examples of the relationship between inflammation and increased cancer risk. (2) Methods: To examine the effects of spontaneous low-grade chronic inflammation on the pathogenesis of CRC, we developed a new murine model of colitis-associated cancer (CAC) by crossing Mucin 2 mutated mice (Winnie) with Apc Min/+ mice. (3) Results: The resulting Winnie-Apc Min/+ model combines an inflammatory background with a genetic predisposition to small intestinal polyposis. Winnie-Apc Min/+ mice show an early occurrence of inflammatory signs and dysplastic lesions in the distal colon with a specific molecular signature. (4) Conclusion: The Winnie-Apc Min/+ model is a perfect model to demonstrate that chronic inflammation represents a crucial risk factor for the onset and progression of tumoral lesions in individuals genetically predisposed to CRC.

Frontiers in Immunology

Mucosal barriers are active sites that encounter a bombardment of antigenic stimuli derived from ... more Mucosal barriers are active sites that encounter a bombardment of antigenic stimuli derived from both the commensal flora and a variety of pathogens, as well as from environmental insults. As such, the ability to mount appropriate innate immune responses is an important first line of defense that confers protection to the host. Central to innate immunity are innate lymphoid cells (ILCs), which were first described a decade ago, and represent a family of heterogeneous cells driven by specific transcription factors and exhibit distinct cytokine profiles that are shared with their CD4+ T-helper cell counterparts. ILCs are particularly enriched at mucosal surfaces, and the tissue microenvironment and cytokine milieu in which ILCs reside are critical factors that drive the behavior and overall function of these cells. In fact, ILCs situated at mucosal barriers must be able to temper their response to a constant exposure of environmental antigens, but also promptly react to pathogens or s...