Swarming motility in host defense

doi:10.1126/science.abj3065

GSTDTAP > 气候变化

DOI	10.1126/science.abj3065
	Swarming motility in host defense
	Briana L. Rocha-Gregg; Anna Huttenlocher
	2021-06-18
发表期刊	Science
出版年	2021
英文摘要	Swarming is a collective movement that has far-reaching implications in biology and beyond. Swarms involve groups of individuals coordinating their behavior in a self-organizing process. Examples include swarming motility and quorum sensing in bacteria ([ 1 ][1]), foraging in ants, and the defensive actions of honey bees. In the animal immune system, swarms of white blood cells called neutrophils respond to microbial threats and tissue damage by traveling en masse to affected tissues. Although much work has been done to understand the initiation of neutrophil swarms ([ 2 ][2]), less is known about how they are terminated. On page 1303 of this issue, Kienle et al. ([ 3 ][3]) reveal that neutrophils limit their swarms by deactivating their own receptors that detect self-produced swarm signals. This desensitization limits neutrophil aggregation and, crucially, promotes pathogen clearance and resolution of acute inflammatory responses. In response to infection or injury, neutrophils often travel long distances through complex chemical landscapes and diverse physical architectures. The long-range signals that initiate neutrophil recruitment to injured or infected tissues are well characterized ([ 4 ][4]) and include the modified lipid leukotriene B4 (LTB4) and chemokines such as interleukin-8 and CXCL2 (C-X-C motif chemokine ligand 2). As they migrate, neutrophils produce and secrete these same attractants, which amplify the recruitment signal and ensure that continued waves of neutrophils reach tissue damage through swarming migration ([ 5 ][5]). Indeed, a recent study identified a quorum-sensing type of neutrophil swarming toward zebrafish wounds through the local propagation of calcium signals and LTB4 release ([ 6 ][6]). This self-amplification is reminiscent of amoeba cells ( Dictyostelium discoideum ) and metastatic cancer cells. Studies of their migration through microfluidic mazes identified the diffusion and breakdown of attractants ([ 7 ][7]) as sources of self-generated chemoattractant gradients that contribute to these coordinated, self-propagated behaviors. Given that neutrophil swarms are self-reinforced, how are they terminated? This is an intriguing question because recruitment signals persist even as neutrophils simultaneously arrive and leave damaged tissues—the latter by reverse migration ([ 4 ][4]). There has been growing interest in identifying pathways and mechanisms that promote resolution of neutrophilic inflammation. A number of neutrophil extrinsic, anti-inflammatory factors, including lipoxins and resolvins ([ 8 ][8]), are generated at injury sites and dampen neutrophil-mediated inflammation. Additionally, the production of reactive oxygen species (ROS) by host cells is necessary for defense against pathogens but also provides a cue that limits inflammation fueled by neutrophils. Chronic granulomatous disease (CGD) patients deficient in ROS production have sustained sterile (pathogen-free) inflammation, and their neutrophils form larger neutrophil swarms in vitro ([ 9 ][9]). Macrophages, another white blood cell present in wounds, cloak damage signals and prevent neutrophil swarming ([ 10 ][10]). They can also promote the reverse migration of neutrophils from sites of tissue damage ([ 11 ][11]). ![Figure][12] Self-balancing act Neutrophils swarm to affected tissue to sequester and kill invading microbes. Pathogen clearance depends on the balance between self-amplification and self-limitation of swarm signals [such as leukotriene B4 (LTB4)]. As neutrophils reach afflicted tissues, the concentration of swarm signals increases. As a result, cognate receptors are desensitized by G protein–coupled receptor kinase 2 (GRK2)–mediated phosphorylation. This ensures that neutrophils pause their motility and sequester and kill pathogens. GRAPHIC: N. DESAI/ SCIENCE Kienle et al. have identified an elegant, neutrophil-intrinsic mechanism that limits swarm size: negative regulation of the receptors that recognize self-produced swarm signals (see the figure). Notably, only receptors for intermediate-target attractants, like LTB4, are affected. Receptors for end-target attractants like C5a (complement component 5a) are unaffected. As a result, neutrophils remain sensitive to exogenous signals that promote functions necessary for pathogen killing. This self-limiting mechanism occurs through the activity of a cytoplasmic GRK-family protein, GRK2 (G protein–coupled receptor kinase 2). GRK proteins are cytoplasmic enzymes that phosphorylate activated G protein–coupled receptors. This phosphorylation results in receptor desensitization and, in some cases, internalization. Internalized receptors can be degraded or returned to the cell surface, as is the case with the CXCL2 receptor but not the LTB4 receptor. In this way, a cell can dynamically alter its sensitivity to various ligands. It is tempting to think that by increasing swarms, more neutrophils would reach the wound, and the magnitude of their combined defenses would easily overcome the threat. This is not always the case. A particularly surprising observation by Kienle et al. is that persistent swarming did not result in better control of infection in mice with neutrophils lacking GRK2. In these animals, both increased cell speed and larger neutrophil clusters were observed at the wound. Without an adequate pause in motility, these neutrophils could not mount a successful defense response. Thus, a cell-intrinsic mechanism ensures that neutrophils successfully transition from the recruitment phase to the defensive phase. The study also suggests that a bigger swarm is not necessarily better in clearing pathogens. This is similar to what is seen in patients with CGD, where increased neutrophil swarming is associated with impaired microbial killing, although these effects may not be related. Not all cellular swarms are beneficial to the body. Excessive or inappropriate neutrophilic inflammation is associated with debilitating diseases, including CGD and other autoinflammatory disorders. Additionally, the collective migration of cancer cells can drive metastasis, and self-propagating swarming may promote this behavior. Given the variety of contexts in which swarms occur, insights into their termination are of great general interest as well. Insect swarms can be both beneficial (bees) and devastatingly costly to agriculture (locusts). For decades, engineers and computer scientists have worked to incorporate aspects of swarm intelligence into technological applications. Robot swarms show promise in a variety of contexts, including environmental remediation ([ 12 ][13]). At first glance, the model of self-control suggested by Kienle et al. seems deceptively simple. Long-range alarm signals trigger self-propagating neutrophil swarms that converge at sources of infection or injury. However, these swarms are intrinsically transient if receptors become desensitized as ligand concentrations increase close to target sites. The selectivity of this response enables neutrophils to prioritize signals that induce effector functions essential for clearing the infection and limiting collateral tissue damage. It is unclear how neutrophils prioritize signals to arrive at and depart from damaged tissues simultaneously ([ 4 ][4]). A tissue factor—myeloid-derived growth factor—has recently been identified that promotes neutrophil reverse migration and limits neutrophil inflammation ([ 13 ][14]). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/330799
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Briana L. Rocha-Gregg,Anna Huttenlocher. Swarming motility in host defense[J]. Science,2021.
APA	Briana L. Rocha-Gregg,&Anna Huttenlocher.(2021).Swarming motility in host defense.Science.
MLA	Briana L. Rocha-Gregg,et al."Swarming motility in host defense".Science (2021).