Gut Microbial Dysbiosis Due to Helicobacter Drives an Increase in Marginal Zone B Cells in the Absence of IL-10 Signaling in Macrophages.
It is clear that IL-10 plays an essential role in maintaining homeostasis in the gut in response to the microbiome. However, it is unknown whether IL-10 also facilitates immune homeostasis at distal sites. To address this question, we asked whether splenic immune populations were altered in IL-10-deficient (Il10(-/-)) mice in which differences in animal husbandry history were associated with susceptibility to spontaneous enterocolitis that is microbiome dependent. The susceptible mice exhibited a significant increase in splenic macrophages, neutrophils, and marginal zone (MZ) B cells that was inhibited by IL-10 signaling in myeloid, but not B cells. The increase in macrophages was due to increased proliferation that correlated with a subsequent enhancement in MZ B cell differentiation. Cohousing and antibiotic treatment studies suggested that the alteration in immune homeostasis in the spleen was microbiome dependent. The 16S rRNA sequencing revealed that susceptible mice harbored a different microbiome with a significant increase in the abundance of the bacterial genus Helicobacter. The introduction of Helicobacter hepaticus to the gut of nonsusceptible mice was sufficient to drive macrophage expansion and MZ B cell development. Given that myeloid cells and MZ B cells are part of the first line of defense against blood-borne pathogens, their increase following a breach in the gut epithelial barrier would be protective. Thus, IL-10 is an essential gatekeeper that maintains immune homeostasis at distal sites that can become functionally imbalanced upon the introduction of specific pathogenic bacteria to the intestinal track.
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
Avijit
A
Ray
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
Sreemanti
S
Basu
Bioinformatics Services Division, Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC 28223; Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC 28223;
Raad Z
RZ
Gharaibeh
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211;
Lydia C
LC
Cook
Center for Clinical and Translational Sciences, University of Alabama at Birmingham, Birmingham, AL 35233;
Ranjit
R
Kumar
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham AL 35233;
Elliot J
EJ
Lefkowitz
Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom;
Catherine R
CR
Walker
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233;
Casey D
CD
Morrow
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211;
Craig L
CL
Franklin
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
Terrence L
TL
Geiger
Division of Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226.
Nita H
NH
Salzman
Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC 28223;
Anthony
A
Fodor
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201; bonnie.dittel@bcw.edu.
Bonnie N
BN
Dittel
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D004269:DNA, Bacterial / Q000235:genetics; D064806:Dysbiosis / Q000382:microbiology*; D004760:Enterocolitis / Q000276:immunology / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D044923:Helicobacter hepaticus / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000276:immunology
D004269:DNA, Bacterial; C556062:IL10 protein, mouse; D012336:RNA, Ribosomal, 16S; D016753:Interleukin-10