The Dynamics of Signaling as a Pharmacological Target

Behar, Marcelo; Barken, Derren; Werner, Shannon L.; Hoffmann, Alexander

doi:10.1016/j.cell.2013.09.018

Cited by 126 publications

(130 citation statements)

References 41 publications

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“…Manipulating signal activation intervals can interfere with signaling dynamics and ultimately hamper and inhibit a protective response, as also shown in recent in vitro experimental and modeling studies (26,27,98,99,110). Our results show that the same principle can affect granuloma outcome in silico and, potentially, in vivo.…”

Section: Fig 4 Granuloma Polarization Ratio (R Gpsupporting

confidence: 52%

“…1E). Increasing the length of these intervals translates into a more sustained signal, which can disrupt "normal" signaling dynamics driving an efficient inflammatory response; this has been demonstrated in both experimental and modeling studies of the NF-B pathway (26,98,99,110). During granuloma formation and development, there is a sustained level of TNF present.…”

Section: Discussionmentioning

confidence: 99%

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Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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Section: Fig 4 Granuloma Polarization Ratio (R Gpsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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“…These findings may well extend to other transcriptional networks as nuclear transport is a defining feature of many gene regulatory networks. Understanding the specific contributions of each process as well as their characteristic time scales is an important step for identifying effective druggable targets that may allow for correction of dynamic misregulation in cells associated with pathology [15].…”

Section: Discussionmentioning

confidence: 99%

“…Mathematical models were shown to recapitulate these dynamic features [8,9], and reduced models have identified NFkB-responsive expression of IkBa as a key determinant of oscillatory dynamics [10][11][12]. The dynamics of NFkB signalling are stimulus-specific, and a critical determinant of inflammatory and immune gene expression programmes [13,14], prompting pioneering work to focus drug-targeting strategies on dynamical features to achieve superior specificity [15].…”

Section: Introductionmentioning

confidence: 99%

Anatomy of a negative feedback loop: the case of I κ B α

Fagerlund

Behar

Fortmann

et al. 2015

J. R. Soc. Interface.

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The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NFkB signalling pathway, a key negative feedback regulator is IkBa. We show here that, contrary to current understanding, NFkB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFkB signalling to identify IkBa molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IkBa and the IkBa-NFkB complex, as well as the free IkBa half-life, as key determinants of post-induction repression of NFkB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.

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“…Other mechanisms such as regulated receptor trafficking in TGF-b pathway [31] or three-state regulation on signalling molecule IKK in NFkB signalling [32,33] may also lead to adaptive responses. Negative feedback is known for its role in reducing fluctuations [22] and speeding up cellular responses [34].…”

Section: Discussionmentioning

confidence: 99%

Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling

Hong

Fung

Zhang

et al. 2015

J. R. Soc. Interface.

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Temporal dynamics of morphogen-driven signalling events are critical for proper embryonic development. During development, cells translate extracellular bone morphogenetic protein (BMP) gradients, often subject to noise, into graded intracellular tail-phosphorylated SMAD (TP-SMAD) levels. Using modelling and experimental approaches, we found that BMPs induce TP-SMAD responses in neural precursor cells in a concentration-dependent manner, which are semi-adaptive within a specific intermediate range of BMP concentration. These semi-adaptive TP-SMAD responses involve an intrinsically slow deactivation of BMP receptors, which attenuates noise by prolonging SMAD deactivation time after BMP withdrawal, but increases response time. Interestingly, negative feedback on BMP receptors is also required for semi-adaptation, which benefits both noise attenuation and response time, and therefore balances the trade-off seen with slow BMP receptor deactivation. These results highlight the rich dynamics of SMAD regulation in response to graded BMP concentration, and elucidate general design principles for balancing noise attenuation and activation speed in signalling systems.

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The Dynamics of Signaling as a Pharmacological Target

Cited by 126 publications

References 41 publications

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Anatomy of a negative feedback loop: the case of I κ B α

Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling

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