Microbiota-dependent signals are required to sustain TLR-mediated immune responses
Lehn K. Weaver, Danielle Minichino, Chhanda Biswas, Niansheng Chu, Jung-Jin Lee, Kyle Bittinger, Sabrin Albeituni, Kim E. Nichols, Edward M. Behrens
Lehn K. Weaver, Danielle Minichino, Chhanda Biswas, Niansheng Chu, Jung-Jin Lee, Kyle Bittinger, Sabrin Albeituni, Kim E. Nichols, Edward M. Behrens
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Research Article Inflammation

Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Abstract

Host-commensal interactions are critical for the generation of robust inflammatory responses, yet the mechanisms leading to this effect remain poorly understood. Using a murine model of cytokine storm, we identified that host microbiota are required to sustain systemic TLR-driven immune responses. Mice treated with broad-spectrum antibiotics or raised in germ-free conditions responded normally to an initial TLR signal but failed to sustain production of proinflammatory cytokines following administration of repeated TLR signals in vivo. Mechanistically, host microbiota primed JAK signaling in myeloid progenitors to promote TLR-enhanced myelopoiesis, which is required for the accumulation of TLR-responsive monocytes. In the absence of TLR-enhanced monocytopoiesis, antibiotic-treated mice lost their ability to respond to repeated TLR stimuli and were protected from cytokine storm–induced immunopathology. These data reveal priming of TLR-enhanced myelopoiesis as a microbiota-dependent mechanism that regulates systemic inflammatory responses and highlight a role for host commensals in the pathogenesis of cytokine storm syndromes.

Authors

Lehn K. Weaver, Danielle Minichino, Chhanda Biswas, Niansheng Chu, Jung-Jin Lee, Kyle Bittinger, Sabrin Albeituni, Kim E. Nichols, Edward M. Behrens

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Figure 6

Unique bacterial taxa are differentially abundant between protected and susceptible mice.

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Unique bacterial taxa are differentially abundant between protected and ...
The stool samples described in Figure 5 were analyzed to determine if unique microbiota taxa were differentially abundant between the identified groups of protected, partially protected, and susceptible mice. (A) A taxonomic heatmap was created to display the abundance of individual microbial taxa identified in the 16S rRNA marker gene sequencing analysis. Each column of the heatmap represents 1 sample, and each row represents 1 taxon, typically a genus. Taxa were included in the chart if the abundance in any sample exceeded 1%. The chart is colored white if taxa were not observed in the sample, dark blue if taxa were observed at very low abundance, and abundance values exceeding 40% are colored red, indicating an extremely dominant species. This allows the reader to quickly survey presence/absence of individual microbial taxa in addition to identifying dominant species within individual samples. (B and C) Taxa were tested for differential abundance if their mean abundance was greater than 1%. Each of the 12 taxa tested in this analysis are displayed in individual plots separating samples based on whether they were obtained from a mouse classified as protected, partially protected, or susceptible to TLR9 cytokine storm (B). Linear regression was employed to test the association between log(proportion) of the taxon and study groups.