Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response

Allen, Nancy C.; Philip, Naomi H.; Hui, Lucy; Zhou, Xu; Franklin, Ruth A.; Kong, Yong; Medzhitov, Ruslan

doi:10.1126/scisignal.aau1851

Cited by 34 publications

(26 citation statements)

References 36 publications

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“…It is therefore possible that in vivo , some of the observed heterogeneity and specialization is location dependent. In addition to genetic and local regulation, recent work has highlighted how metabolic state and circadian rhythm have profound effects on macrophage functions 40–42 . It is possible that differences in metabolic states and molecular clocks help generate the diversity required to induce partially specialized macrophages after co-stimulation.…”

Section: Discussionmentioning

confidence: 99%

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Muñoz-Rojas

Kelsey

Pappalardo

et al. 2020

Preprint

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14Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and 15 maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve 16 potentially conflicting cues in the microenvironment via mechanisms that remain unclear. Here, 17we used single-cell RNA sequencing to explore how individual macrophages respond when co-18 stimulated with the inflammatory stimuli, LPS+IFN-γ, and the resolving cytokine, IL-4. We found 19 that co-stimulated macrophages displayed a distinct global transcriptional program. However, 20 variable negative cross-regulation between some LPS+IFN-γ-and IL-4-specific genes resulted in 21 significant cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation led 22to mutually exclusive expression of the T-cell-polarizing cytokines Il6 and Il12b versus the IL-4-23 associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion 24 measurements showed that these specialized functions were maintained for at least 48 hours. 25Overall, our study suggests that increasing functional diversity in the population is one strategy 26 macrophages use to respond to conflicting environmental cues. 27 LPS+IFN-γ or the IL-4 transcriptional program in response to co-stimulation. 131 132 Co-stimulation with LPS+IFN-γ and IL-4 induces transcriptional cross-regulation that 133 varies substantially across individual cells 134We next focused on how co-stimulation with LPS+IFN-γ and IL-4 affected the expression 135 of genes uniquely upregulated by either LPS+IFN-γ or IL-4 alone ( Fig. 2a), which we refer to as 136 the core gene programs. For both LPS+IFN-γ-and IL-4-induced genes, co-stimulation with the 137 other cue caused both transcriptional upregulation and inhibition in a subset of core genes 138 belonging to each program, consistent with our own and previously reported observations 14 . 139Among the LPS+IFN-γ-induced core genes, 87 were inhibited by co-stimulation and 97 were 140 augmented by co-stimulation, while among the IL-4-induced core genes, 196 were inhibited and 141 16 were augmented by co-stimulation (Fig. 2b). 142We compared observations from our single-cell dataset to population-level RT-qPCR data 514

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Section: Discussionmentioning

confidence: 99%

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Muñoz-Rojas

Kelsey

Pappalardo

et al. 2020

Preprint

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“…For a poorly-managed herd, if the vaccination date was unknown (or not vaccinated), represented hypothetically as the gray band of C6 in Fig 4b, a randomly picked date could be used as Tb1. The T0 could be anywhere from 10 to 28 dpv, partially affected by the individual immune status 20 . We recommended a 3-5 day interval between T0 and Ta1 and Tax (x=60/interval) so a detailed IgG serodynamic curve could be obtained, which would be informative for deducing the position T0.…”

Section: Iggsmentioning

confidence: 99%

Epitope containing short peptides capture distinct IgG serodynamics that enable DIVA for live-attenuated vaccines

Xue

Liu

et al. 2019

Preprint

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Differentiating infected from vaccinated animals (DIVA) strategies have been central enabling techniques in several successful viral disease elimination programs. However, owing to their long and uncertain development process, no DIVA-compatible vaccines are available for many important diseases. We report herein a new DIVA strategy based on hybrid protein-peptide microarrays which can theoretically work with any vaccine. Leading from our findings from Peste des petits ruminants (PPR), we found 4 epitope containing short peptides (ECSPs) which have distinct IgG serodynamics: anti-ECSP IgGs only exist for 10-60 days post vaccination (dpv), while anti-protein IgGs remained at high levels for >1000 dpv. These data enabled design of a DIVA diagnostic microarray containing 4 ECSPs and 3 proteins, which unlike cELISA and VNT, enables ongoing monitoring of serological differences between vaccinated individuals and individuals exposed to the pathogen. For 50 samples after 60 dpv, 20 animals were detected with positive anti-ECSP IgGs, indicating recent infections in vaccinated goat/sheep herds. These DIVA diagnostic microarrays will almost certainly facilitate eradication programs for (re-)emerging pathogens and zoonoses.

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“…In addition to examining the impact of the host clock on the IDC, we also test whether infection of clock-disrupted mice has fitness consequences for both parasites and hosts. The mammalian clock controls many aspects of immunity [29], including the ability of leukocytes to migrate to the tissues [30] and the ability of macrophages to release cytokines [31], and rodents without functioning Per2 lack IFN-y mRNA cycling in the spleen (a key organ for malaria parasite clearance) and have decreased levels of pro-inflammatory cytokines in blood serum [32]. Thus, we predicted that parasites will achieve higher densities, and hosts experience more severe disease, in Per1/2 -null compared to wild type mice.…”

Section: Introductionmentioning

confidence: 99%

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

O’Donnell

Prior

Reece

2019

Preprint

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SUMMARYCircadian clocks coordinate organisms’ activities with daily cycles in their environment. Parasites are subject to daily rhythms in the within-host environment, resulting from clock-control of host behaviours and physiologies, including immune responses. Parasites also exhibit rhythms in within-host activities; the timing of host feeding sets the timing of the within-host replication of malaria parasites. Why host feeding matters to parasites and how coordination with feeding is achieved are unknown. Determining whether parasites coordinate with clock-driven food-related rhythms of their hosts matters because rhythmic replication underpins disease symptoms and fuels transmission.We find that parasite rhythms became coordinated with the time of day that hosts feed in both wild type and clock-mutant mice, whereas parasite rhythmicity was lost in clock-mutant mice that fed continuously. These patterns occurred regardless of whether infections were initiated with synchronous or with desynchronised parasites.Malaria parasite rhythms are not driven by canonical clock-controlled host rhythms. Instead, we propose parasites coordinate with a temporally-restricted nutrient that becomes available through host digestion or are influenced by a separate clock-independent host process that directly responds to feeding. Thus, interventions could disrupt parasite rhythms to reduce their fitness, without interference by host clock-controlled-homeostasis.

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Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response

Cited by 34 publications

References 36 publications

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Epitope containing short peptides capture distinct IgG serodynamics that enable DIVA for live-attenuated vaccines

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

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