Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection

Jose, Shinsmon; Abhyankar, Mayuresh M.; Mukherjee, Avijit; Xue, Jianli; Andersen, Heidi; Madan, Rajat

doi:10.1038/mi.2017.119

Cited by 9 publications

(26 citation statements)

References 48 publications

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“…Excessive colonic tissue injury is associated with worse disease outcomes after CDI [31]. To understand the role of MIF in controlling CDI-induced damage, we assessed colonic tissue both macroscopically and microscopically.…”

Section: Resultsmentioning

confidence: 99%

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Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

et al. 2018

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Clostridium difficile is an important cause of nosocomial diarrhea in the western world. Toxins (A, B, and binary toxins) generated by C. difficile bacteria damage intestinal epithelial cells. Hallmarks of host response to C. difficile infection (CDI) include upregulation of inflammatory mediators and tissue infiltration by immune cells. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that is known to enhance the host immune response to infectious pathogens. Additionally, MIF can adversely impact host survival to numerous infections. The role of MIF in the pathogenesis of CDI remains poorly understood. Here, we show that patients with CDI had significantly higher circulating MIF compared to patients who had diarrhea but tested negative for C. difficile (non-CDI controls). Similarly, in a mouse model, C. difficile challenge significantly increased levels of plasma and tissue MIF. Antibody-mediated depletion of MIF decreased C. difficile-induced inflammatory responses, clinical disease, and mortality. Together, these results uncover a potential role for MIF in exacerbating CDI and suggest that use of anti-MIF antibodies may represent a therapeutic strategy to curb host inflammatory responses and improve disease outcomes in CDI.

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Section: Resultsmentioning

confidence: 99%

“…In CDI, an over exuberant host inflammatory response predominated by neutrophils is typically associated with worse disease outcomes [10, 31]. We thus examined the effects of MIF neutralization on host inflammation in cecal tissue collected from mice after CDI.…”

Section: Resultsmentioning

confidence: 99%

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

et al. 2018

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“…However, after neutrophil extravasation into colonic lumen, CD11b binding to epithelial cells can also promote mucosal healing (Sumagin et al, 2016). We have previously observed that despite similar pathogen load or C. difficile toxin titers in QQ and RR mice, the latter group had more colonic tissue damage (Jose et al, 2018a). But, RR mice that survived the initial insult had improved histology scores and faster disease resolution later on (Jose et al, 2018a).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that host genetic make-up impacts CDI-induced tissue neutrophilia: homozygosity for a common single nucleotide polymorphism (SNP) in leptin receptor (LEPR), rs1137101, that results in a change of amino acid at position 223 of LEPR from Glutamine [Q] to Arginine [R] ( Duggal et al, 2011 ), is also associated with an over-exuberant neutrophil response ( Jose et al, 2018a ). We found that: ( i ) prior to infection, mice with the mutant/derived LEPR allele (RR) did not exhibit any obvious differences compared to those that express the wildtype allele (QQ); ( ii ) after CDI, both groups had similar pathogen burden and toxin titers, but RR mice had more systemic and tissue neutrophils; and ( iii ) RR humans with CDI had exaggerated peripheral blood leukocytosis, compared to QQ/QR ( Jose et al, 2018a ). Thus, CDI uncovers a hyper-inflammatory phenotype in the RR host that is manifested as exaggerated blood and colonic neutrophilia.…”

Section: Introductionmentioning

confidence: 99%

Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

Horrigan

Jose

Mukherjee

et al. 2021

Front. Cell. Infect. Microbiol.

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Neutrophils are key first-responders in the innate immune response to C. difficile infection (CDI) and play a central role in disease pathogenesis. Studies have clearly shown that tissue neutrophil numbers need to be tightly regulated for optimal CDI outcomes: while excessive colonic neutrophilia is associated with severe CDI, neutrophil depletion also results in worse outcomes. However, the biological mechanisms that control CDI-induced neutrophilia remain poorly defined. C-X-C chemokine receptor 2 (CXCR2) is a chemotactic receptor that is critical in neutrophil mobilization from bone marrow to blood and tissue sites. We have previously reported that a single nucleotide polymorphism (SNP) in leptin receptor (LEPR), present in up to 50% of people, influenced CDI-induced neutrophil CXCR2 expression and tissue neutrophilia. Homozygosity for mutant LEPR (i.e. RR genotype) was associated with higher CXCR2 expression and more tissue neutrophils. Here, we investigated the biological mechanisms that regulate neutrophil CXCR2 expression after CDI, and the influence of host genetics on this process. Our data reveal that: a) CXCR2 plays a key role in CDI-induced neutrophil extravasation from blood to colonic tissue; b) plasma from C. difficile-infected mice upregulated CXCR2 on bone marrow neutrophils; c) plasma from C. difficile-infected RR mice induced a higher magnitude of CXCR2 upregulation and had more IL-1β; and d) IL-1β neutralization reduced CXCR2 expression on bone marrow and blood neutrophils and their subsequent accrual to colonic tissue. In sum, our data indicate that IL-1β is a key molecular mediator that communicates between gastro-intestinal tract (i.e. site of CDI) and bone marrow (i.e. primary neutrophil reservoir) and regulates the intensity of CDI-induced tissue neutrophilia by modulating CXCR2 expression. Further, our studies highlight the importance of host genetics in affecting these innate immune responses and provide novel insights into the mechanisms by which a common SNP influences CDI-induced neutrophilia.

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“…Jose et al showed that homozygosity for leptin receptor Q223R SNP significantly increases the risk of peak peripheral WBC count >20 × 10 9 /L, which is an indicator of adverse outcomes. They have also demonstrated in a murine model of CDI, that mice homozygous for the same SNP exhibit a higher leukocyte count in blood and tissue, exaggerated tissue inflammation and higher mortality, compared with control mice [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of the High Mobility Group Box 1 (HMGB1) Gene in Peripheral Blood in Patients with Mild or Moderate Clostridioides difficile Infection

et al. 2020

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Cytokines are mediators of inflammation induced in the course of Clostridioides difficile infection (CDI). High Mobility Group Box 1 (HMGB1) is a cytokine playing an important role in the pathogenesis of numerous inflammatory and autoimmune diseases. The aim of the study was to assess the HMGB1 gene expression in the course of CDI. We have performed a prospective case-control study- including 55 adult patients, among them 27 with CDI, who were hospitalized from October 2018 to February 2020 and 28 healthy volunteers. We assessed: a complete blood count with differential leukocyte count, blood creatinine, albumin, and C-reactive protein (CRP) levels. Then, the expression of the HMGB1 gene was evaluated using quantitative Real-Time PCR. Patients with CDI were found to have a significant increase in white blood cells (WBC), neutrophil count, and CRP levels, they also exhibited decreased levels of albumin compared with controls. The HMGB1 gene expression was significantly lower among patients with CDI compared with the control group and significantly, inversely correlated with CRP level in blood. In conclusion, we have observed a decreased expression of the HMGB1 gene in peripheral blood of patients with mild or moderate CDI, which hypothetically could reflect their diminished capability to fight the pathogen.

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Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection

Cited by 9 publications

References 48 publications

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

Decreased Expression of the High Mobility Group Box 1 (HMGB1) Gene in Peripheral Blood in Patients with Mild or Moderate Clostridioides difficile Infection

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