Naresh Singh Redhu - Academia.edu (original) (raw)

Papers by Naresh Singh Redhu

Loss of IL-10R function leads to severe early onset colitis and in murine models is associated wi... more Loss of IL-10R function leads to severe early onset colitis and in murine models is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed Stat1-/- mice exhibit defects in colonic macrophage accumulation following Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNGR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both WT and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R prevents the generation of a cell extrinsic s...

Wiskott-Aldrich syndrome protein (WASP) is a cytoskeletal regulator that is largely restricted to... more Wiskott-Aldrich syndrome protein (WASP) is a cytoskeletal regulator that is largely restricted to hematopoietic cells. While WASP expression in both lymphocytes and macrophages play a critical role in maintaining intestinal homeostasis, the function of WASP in innate lymphoid cells is unknown. Here we analyzed the role of WASP in the differentiation and function of group 3 innate lymphoid cells (ILC3s). WASP-deficient mice (Was-/-) have a marked reduction in ILC3s. Moreover, antimicrobial peptide expression in response to ILC3-derived IL-22 was also reduced in the absence of WASP. In Was-/- mice, we observed a reduction in CCR6+ ILC3s, cells known to restrict immune responses to commensal bacteria. WASP-deficient mice were more susceptible to Citrobacter rodentium, an enteric infection controlled by ILC3s. Interestingly, there was no reduction in ILC3s in Was-/- germ-free mice when compared to WT germ-free mice. ILC3s lacking WASP expression also demonstrated microbially-dependent a...

Scientific Reports, 2022

Macrophages are a heterogeneous population of mononuclear phagocytes abundantly distributed throu... more Macrophages are a heterogeneous population of mononuclear phagocytes abundantly distributed throughout the intestinal compartments that adapt to microenvironmental specific cues. In adult mice, the majority of intestinal macrophages exhibit a mature phenotype and are derived from blood monocytes. In the steady-state, replenishment of these cells is reduced in the absence of the chemokine receptor CCR2. Within the intestine of mice with colitis, there is a marked increase in the accumulation of immature macrophages that demonstrate an inflammatory phenotype. Here, we asked whether CCR2 is necessary for the development of colitis in mice lacking the receptor for IL10. We compared the development of intestinal inflammation in mice lacking IL10RA or both IL10RA and CCR2. The absence of CCR2 interfered with the accumulation of immature macrophages in IL10R-deficient mice, including a novel population of rounded submucosal Iba1+ cells, and reduced the severity of colitis in these mice. In...

Microbiome, 2021

Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how the... more Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was−/−) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was−/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was−/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was−/− mice, ...

The Annals of Thoracic Surgery, 2021

BACKGROUND The airway structures and mRNA expression of genes that regulate airway inflammation a... more BACKGROUND The airway structures and mRNA expression of genes that regulate airway inflammation and remodeling may be altered in the trachea of patients with tracheobronchomalacia (TBM). METHODS Fourteen tracheal specimens from 2005-to-2018 were used in this study. Surgical resection specimens from patients with TBM and tracheal stenosis (TS) were compared to control tracheal specimens obtained from autopsy cases. We investigated the mRNA expression of genes encoding fibroblast growth factor (FGF), binding protein 2 (FGFBP2), FGF receptor R3 (FGFR3), interleukin-1 beta (IL1β), tumor growth factor-beta 1 (TGFβ1), tissue inhibitor of metalloproteinases 1 (TIMP1), and intercellular adhesion molecule 1 (ICAM1), as well as established markers of airway inflammation including interferon-gamma (IFNγ) and tumor necrosis factor (TNF). The relative expression of target transcripts was assessed by qRT-PCR. A histological examination of the same resected airway specimens was performed on formalin-fixed paraffin embedded tissue sections. RESULTS FGFBP2 and FGFR3 showed higher expression in TBM compared to TS and control groups (p<0.05, p<0.01, respectively). Furthermore, both TGFβ1 and TIMP1 were elevated in TBM compared to controls (p<0.05). Conversely, ICAM1 was downregulated in TBM versus TS and controls (p<0.05). IL1β, IFNγ, and TNF were increased in TBM although did not achieve statistical significance. Histologically, compared to control airways, both TBM and TS demonstrated submucosal fibrotic changes, with TBM additionally demonstrating alterations in elastin fiber quality and density in the posterior membrane. CONCLUSIONS Significant changes in gene expression are observed in the tracheal walls of patients with TBM and TS compared to controls.

Pediatric Research, 2021

BACKGROUND: In infants admitted to an ICU with respiratory failure, there is an association betwe... more BACKGROUND: In infants admitted to an ICU with respiratory failure, there is an association between the ratio of CD8 + to CD4 + T cells within the upper respiratory tract and disease severity. Whether this ratio is associated with respiratory disease severity within children presenting to a pediatric emergency department is not known. METHODS: We studied a convenience sample of 63 children presenting to a pediatric emergency department with respiratory symptoms. T cell subsets in the nasal mucosa were analyzed by flow cytometry. We compared CD4 + and CD8 + T cells subsets in these samples and analyzed the proportion of these subsets that expressed markers associated with tissue residency. RESULTS: We were able to identify major subsets of CD8 and CD4 T cells within the nasal mucosa using flocked swabs. We found no difference in the ratio CD8 + to CD4 + T cells in children with upper or lower respiratory illness. A positive association between tissue-resident memory T cell frequency and patient age was identified. CONCLUSIONS: In our patient populations, the CD8 + :CD4 + ratio was not associated with disease severity. The majority of T cells collected on nasal swabs are antigen experienced, and there is an association between the frequency of tissue-resident T cells and age.

Nature communications, Jan 3, 2018

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis.... more Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both W...

Gastroenterology, 2017

Background: The ATP-binding cassette transporter MDR1 is a glycoprotein highly expressed by intes... more Background: The ATP-binding cassette transporter MDR1 is a glycoprotein highly expressed by intestinal epithelial cells and Th17 lymphocytes, and has been linked to experimental colitis and inflammatory bowel disease (IBD). MDR1 mediates efflux of xenobiotics or endogenous metabolites, such as unconjugated bilirubin (UCB). UCB is a product of heme oxidation with known immunosuppressant properties in IBD. UCB modulates the pathogenic potential of Th17 cells, the predominant T-effector subset in IBD, via CD39, an ectonucleotidase converting pro-inflammatory ATP into immunosuppressive adenosine. We have previously shown that in IBD Th17 cells display heightened MDR1 activity, when compared to healthy subjects (HS). Aim: to investigate the effects of ritonavir (RTV), an MDR1 inhibitor, on boosting UCB immunosuppressant properties in experimental colitis and human IBD. Methods: RTV was administered alone or in combination with UCB to wild-type (WT) mice, in which colitis was induced with 3% dextran-sodium-sulfate (DSS), replaced after 7 days with standard water. Th17 cells from peripheral blood-derived CD4 cells of 23 HS (control) and 16 Crohn's disease patients were exposed for the last 36 hours of culture to RTV, alone or in combination with UCB. Th17 cell immunophenotypes, proliferation and suppressive function were studied thereafter. Results: Compared to treatment with UCB, RTV or vehicle, administration of RTV in combination with UCB significantly ameliorated the disease activity index (calculated on the basis of body weight decrease, rectal bleeding and stool consistency) from day 6 during DSS treatment and throughout recovery. This amelioration of colitis was associated with increased colon length, lower histology score, reduction in the frequency of IL-17 + CD4 + cells in the spleen, mesenteric lymph nodes and lamina propria lymphocytes; and increase in the proportion of CD4 cells positive for IL-10, CD39 and FOXP3 within intra epithelial lymphocytes. Such beneficial effects were not noted in CD39-/mice during DSS treatment or recovery. Exposure of control human Th17 cells to RTV and UCB resulted in high levels of CD39 and FOXP3, while diminishing the proportion of proliferating cells and enhancing Th17 suppression over IFNγ and IL-17 production by CD4 + CD25responders. Higher levels of CD39 and FOXP3 were also observed in Th17 cells of Crohn's disease patients, upon exposure to RTV and UCB. Conclusion: MDR1 inhibition enhances UCB immunosuppressant properties in DSS-induced colitis through a mechanism that depends, at least in part, on CD39. Beneficial effects of RTV and UCB are noted in Th17 cells from both HS and Crohn's disease patients, as reflected by induction of high FOXP3 levels and enhanced suppression. Our studies indicate further pathogenetic roles for MDR1 in IBD and provide a potential therapeutic avenue for study in human disease.

eLife, Jul 5, 2017

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory... more Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal peri...

World Journal of Immunology, 2015

Oncotarget, 2016

Airway smooth muscle (ASM) hyperplasia is a key feature of airway remodeling in development of lu... more Airway smooth muscle (ASM) hyperplasia is a key feature of airway remodeling in development of lung diseases such as asthma. Anomalous proliferation of ASM cells directly contributes to ASM hyperplasia. However, the molecular mechanisms controlling ASM cell proliferation are not completely understood. Semaphorins are versatile regulators of various cellular processes including cell growth and proliferation. The role of semaphorins in ASM cell proliferation has remained to be addressed. Here, we report that semaphorin 3A (Sema3A) receptor, neuropilin 1 (Nrp1), is expressed on human ASM cells (HASMC) isolated from healthy and asthmatic donors and treatment of these cells with exogenous Sema3A inhibits growth factor-induced proliferation. Sema3A inhibitory effect on HASMC proliferation is associated with decreased tyrosine phosphorylation of PDGFR, downregulation of Rac1 activation, STAT3 and GSK-3β phosphorylation. Bronchial sections from severe asthmatics displayed immunoreactivity of Nrp1, suggestive of functional contribution of Sema3A-Nrp1 axis in airway remodeling. Together, our data suggest Sema3A-Nrp1 signaling as a novel regulatory pathway of ASM hyperplasia.

Gastroenterology, Dec 27, 2016

IL10 receptor (IL10R)-deficient mice develop spontaneous colitis and similarly, patients with los... more IL10 receptor (IL10R)-deficient mice develop spontaneous colitis and similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease (IBD). Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1 beta (IL1B). We demonstrated that innate immune production of IL1B mediates colitis in IL10R-deficient mice. Transfer of Il1r1(-/-) CD4(+) T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4(+) T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1B through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide (LPS) and adenosine triphosphate stimulation...

Inflammatory bowel diseases, 2016

Rare mutations in IL-10 or its receptors (IL10R) lead to severe very early onset (VEO)/infantile ... more Rare mutations in IL-10 or its receptors (IL10R) lead to severe very early onset (VEO)/infantile IBD in humans suggesting that the IL10/IL10R pathway is indispensable for mucosal immune homeostasis in the developing gut. Mice deficient in IL10/IL10R also develop spontaneous colitis. We recently reported that IL10R signaling in macrophages is critical for mucosal homeostasis in adult mice and humans (Shouval et al, Immunity 2014). However, the identification of IL10-dependent regulatory mechanisms in infants remains elusive. The goal of this study is to dissect key IL10R-dependent mechanisms that initiate mucosal homeostasis in the maturing infant colon. We performed age-dependent analysis of pro- and anti-inflammatory genes expression in the colon of developing littermate Il10rb and Il10rb (control) 129SvEv mice. We analyzed fecal microbiome from 2 to 14 week old control and Il10rb mice using 16S rRNA sequencing. Flow cytometry was performed to assess various lamina propria (LP) imm...

Journal of vector borne diseases, 2007

B109. AIRWAY SMOOTH MUSCLE PHENOTYPE AND FUNCTION, 2009

PLoS ONE, 2012

Background: Pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant funct... more Background: Pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 is produced by immune and structural cells. However, very little is known about the expression of PTX3 and its role in allergic asthma. Objectives and Methods: We sought to determine the PTX3 expression in asthmatic airways and its function in human airway smooth muscle cells (HASMC). In vivo PTX3 expression in bronchial biopsies of mild, moderate and severe asthmatics was analyzed by immunohistochemistry. PTX3 mRNA and protein were measured by real-time RT-PCR and ELISA, respectively. Proliferation and migration were examined using 3 H-thymidine incorporation, cell count and Boyden chamber assays. Results: PTX3 immunoreactivity was increased in bronchial tissues of allergic asthmatics compared to healthy controls, and mainly localized in the smooth muscle bundle. PTX3 protein was expressed constitutively by HASMC and was significantly up-regulated by TNF, and IL-1b but not by Th2 (IL-4, IL-9, IL-13), Th1 (IFN-c), or Th-17 (IL-17) cytokines. In vitro, HASMC released significantly higher levels of PTX3 at the baseline and upon TNF stimulation compared to airway epithelial cells (EC). Moreover, PTX3 induced CCL11/eotaxin-1 release whilst inhibited the fibroblast growth factor-2 (FGF-2)-driven HASMC chemotactic activity. Conclusions: Our data provide the first evidence that PTX3 expression is increased in asthmatic airways. HASMC can both produce and respond to PTX3. PTX3 is a potent inhibitor of HASMC migration induced by FGF-2 and can upregulate CCL11/ eotaxin-1 release. These results raise the possibility that PTX3 may play a dual role in allergic asthma.