Interleukin 10 controls the balance between tolerance, pathogen elimination and immunopathology in birds
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Curated by eLife
eLife Assessment
Despite the conserved anti-inflammatory activity in birds, whether IL-10 also controls avian intestinal homeostasis remains unclear. Generating genetic knockouts, Meunier et al. firmly established that a complete lack of IL-10 strengthened immunity against enteric bacteria in chickens, while also aggravating infection-inflicted tissue damage upon parasite infection. The findings presented in this manuscript are valuable, and the strength of evidence is convincing; however, it is advised that the deficiencies and weaknesses pointed out by all the reviewers are meticulously addressed.
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Abstract
Effective mucosal immunity in the intestine involves a fine balance between tolerance of the microbiome, recognition and elimination of pathogens, and inflammatory tissue injury. The anti-inflammatory cytokine IL10 regulates these processes in the intestines of mice and humans; the anti-inflammatory activity of IL10 is also conserved in birds. To determine the function of IL10 in avian mucosal immunity, we generated germ line modifications of the chicken IL10 locus to abolish or reduce IL10 expression. In vitro analysis of macrophage response to lipopolysaccharide confirmed the loss of IL10 protein expression, the lack of dosage compensation in heterozygotes, and prevention of autocrine inhibition of nitric oxide production in homozygous IL10 knockout macrophages. IL10-deficiency significantly altered the composition of the caecal microbiome, but unlike IL10-deficient mice and humans, IL10-deficient chickens did not exhibit spontaneous colitis. Following experimental challenge with Salmonella enterica serovar Typhimurium or Campylobacter jejuni in IL10-deficient chickens, enhanced clearance of the pathogens was associated with elevated transcription of pro-inflammatory genes and increased infiltration of inflammatory cells into gut mucosa. In IL10-deficient chickens challenged with the parasite Eimeria tenella, pathogen clearance was accelerated but caecal lesions were more severe and weight gain was compromised. Neither the heterozygous IL10 knockout nor a homozygous IL10 enhancer mutation had a major effect on pathogen clearance or inflammation in any of the challenge models. Our findings highlight the intrinsic compromise in mucosal immune response and have important implications for the development of strategies to combat avian and zoonotic pathogens in poultry.
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eLife Assessment
Despite the conserved anti-inflammatory activity in birds, whether IL-10 also controls avian intestinal homeostasis remains unclear. Generating genetic knockouts, Meunier et al. firmly established that a complete lack of IL-10 strengthened immunity against enteric bacteria in chickens, while also aggravating infection-inflicted tissue damage upon parasite infection. The findings presented in this manuscript are valuable, and the strength of evidence is convincing; however, it is advised that the deficiencies and weaknesses pointed out by all the reviewers are meticulously addressed.
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Reviewer #1 (Public review):
Summary:
In this study, Meunier et al. investigated the functional role of IL-10 in avian mucosal immunity. While the anti-inflammatory role of IL-10 is well established in mammals, and several confirmatory knockout models are available in mice, IL-10's role in avian mucosal immunity is so far correlative. In this study, the authors generated two different models of IL-10 ablation in Chickens. A whole body knock-out model and an enhancer KO model leading to reduced IL10 expression. The authors first performed in vitro LPS stimulation-based experiments, and then in vivo two different infection models employing C. jejuni and E. tenella, to demonstrate that complete ablation of IL10 leads to enhanced inflammation-related pathology and gene expression, and enhanced pathogen clearance. At a steady-state level, …
Reviewer #1 (Public review):
Summary:
In this study, Meunier et al. investigated the functional role of IL-10 in avian mucosal immunity. While the anti-inflammatory role of IL-10 is well established in mammals, and several confirmatory knockout models are available in mice, IL-10's role in avian mucosal immunity is so far correlative. In this study, the authors generated two different models of IL-10 ablation in Chickens. A whole body knock-out model and an enhancer KO model leading to reduced IL10 expression. The authors first performed in vitro LPS stimulation-based experiments, and then in vivo two different infection models employing C. jejuni and E. tenella, to demonstrate that complete ablation of IL10 leads to enhanced inflammation-related pathology and gene expression, and enhanced pathogen clearance. At a steady-state level, however, IL-10 ablation did not lead to spontaneous colitis.
Strengths:
Overall, the study is well executed and establishes an anti-inflammatory role of IL-10 in birds. While the results are expected and not surprising, this appears to be the first report to conclusively demonstrate IL-10's anti-inflammatory role upon its genetic ablation in the avian model. Provided this information is applicable in combating pathogen infection in livestock species in sustainable industries like poultry, the study will be of interest to the field.
Weaknesses:
The study is primarily a confirmation of the already established anti-inflammatory role of IL-10.
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Reviewer #2 (Public review):
Summary:
The authors were to investigate the functional role of IL10 on mucosal immunity in chickens. CRISPR technology was employed to generate IL10 knock-out chickens in both exon and putative enhancer regions. IL10 expressions were either abolished (knockout in exon) or reduced (enhancer knock-out). IL-10 plays an important role in the composition of the caecal microbiome. Through various enteric pathogen challenges, deficient IL10 expression was associated with enhanced pathogen clearance, but with more severe lesion scores and body weight loss.
Strengths:
Both in vitro and in vivo knock-out abolished and reduced IL10 expression, and broad enteric pathogens were challenged in vivo, and various parameters were examined to evaluate the functional role of IL10 on mucosal immunity.
Weaknesses:
Overexpression …
Reviewer #2 (Public review):
Summary:
The authors were to investigate the functional role of IL10 on mucosal immunity in chickens. CRISPR technology was employed to generate IL10 knock-out chickens in both exon and putative enhancer regions. IL10 expressions were either abolished (knockout in exon) or reduced (enhancer knock-out). IL-10 plays an important role in the composition of the caecal microbiome. Through various enteric pathogen challenges, deficient IL10 expression was associated with enhanced pathogen clearance, but with more severe lesion scores and body weight loss.
Strengths:
Both in vitro and in vivo knock-out abolished and reduced IL10 expression, and broad enteric pathogens were challenged in vivo, and various parameters were examined to evaluate the functional role of IL10 on mucosal immunity.
Weaknesses:
Overexpression of IL-10 either in vitro or in vivo may further support the findings from this study.
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