The role of Rab27a in the regulation of neutrophil function

Catz, Sergio D.

doi:10.1111/cmi.12328

Cited by 32 publications

(29 citation statements)

References 72 publications

(147 reference statements)

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“…Interestingly, intraphagosomal ROS production and phagosomal maturation were unaffected in Rab27a‐KO neutrophils, reiterating that although Munc13‐4 is a well‐established Rab27a effector, it has various Rab27a‐independent functions as well (Fig. ) (the possible role of Rab27a and Munc13‐4 in phagosomal maturation was reviewed before and is beyond the scope of this work).…”

Section: The Role Of Vesicular Trafficking Regulatory Proteins In Thementioning

confidence: 67%

Molecular mechanisms regulating secretory organelles and endosomes in neutrophils and their implications for inflammation

Ramadass

Catz

2016

Immunological Reviews

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Neutrophils constitute the first line of cellular defense against invading microorganisms and modulate the subsequent innate and adaptive immune responses. In order to execute a rapid and precise response to infections, neutrophils rely on preformed effector molecules stored in a variety of intracellular granules. Neutrophil granules contain microbicidal factors, the membrane-bound components of the respiratory burst oxidase, membrane-bound adhesion molecules, and receptors that facilitate the execution of all neutrophil functions including adhesion, transmigration, phagocytosis, degranulation, and neutrophil extracellular trap formation. The rapid mobilization of intracellular organelles is regulated by vesicular trafficking mechanisms controlled by effector molecules that include small GTPases and their interacting proteins. In this review, we focus on recent discoveries of mechanistic processes that are at center stage of the regulation of neutrophil function, highlighting the discrete and selective pathways controlled by trafficking modulators. In particular, we describe novel pathways controlled by the Rab27a effectors JFC1 and Munc13-4 in the regulation of degranulation, reactive oxygen species and neutrophil extracellular trap production, and endolysosomal signaling. Finally, we discuss the importance of understanding these molecular mechanisms in order to design novel approaches to modulate neutrophil-mediated inflammatory processes in a targeted fashion.

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Section: The Role Of Vesicular Trafficking Regulatory Proteins In Thementioning

confidence: 67%

Molecular mechanisms regulating secretory organelles and endosomes in neutrophils and their implications for inflammation

Ramadass

Catz

2016

Immunological Reviews

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“…Upon stimulation, neutrophils will mobilize their granules, which will fuse with either the cytoplasmic membrane or the phagosomal membrane, ultimately resulting in functional responses, including exocytosis, extravasation, phagocytosis, and elimination of various microorganisms (56)(57)(58). Several neutrophil responses, including exocytosis, chemotaxis, respiratory burst activity, and chemokine synthesis, are mediated through the p38 MAPK pathway (33).…”

Section: Discussionmentioning

confidence: 99%

Filifactor alocis Promotes Neutrophil Degranulation and Chemotactic Activity

et al. 2016

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Filifactor alocis is a recently recognized periodontal pathogen; however, little is known regarding its interactions with the immune system. As the first-responder phagocytic cells, neutrophils are recruited in large numbers to the periodontal pocket, where they play a crucial role in the innate defense of the periodontium. Thus, in order to colonize, successful periodontal pathogens must devise means to interfere with neutrophil chemotaxis and activation. In this study, we assessed major neutrophil functions, including degranulation and cell migration, associated with the p38 mitogen-activated protein kinase (MAPK) signaling pathway upon challenge with F. alocis. Under conditions lacking a chemotactic gradient, F. alocischallenged neutrophils had increased migration compared to uninfected cells, indicating that F. alocis increases chemokinesis in human neutrophils. In addition, neutrophil chemotaxis induced by interleukin-8 was significantly enhanced when cells were challenged with F. alocis, compared to noninfected cells. Similar to live bacteria, heat-killed F. alocis induced both random and directed migration of human neutrophils. The interaction of F. alocis with Toll-like receptor 2 induced granule exocytosis along with a transient ERK1/2 and sustained p38 MAPK activation. Moreover, F. alocis-induced secretory vesicle and specific granule exocytosis were p38 MAPK dependent. Blocking neutrophil degranulation with TAT-SNAP23 fusion protein significantly reduced the chemotactic and random migration induced by F. alocis. Therefore, we propose that induction of random migration by F. alocis will prolong neutrophil traffic time in the gingival tissue, and subsequent degranulation will contribute to tissue damage.

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“…However, since Rab27a has been implicated in neutrophil degranulation as well as in other process that can impinge on immune function1314, it was important to use additional approaches to evaluate exosomes as drivers of T cell activation during an in vivo Mtb infection. For this objective we generated BCG or Mtb H37Rv strains that expresses tagged DsRed or the mycobacterial protein HspX which differed in their trafficking to exosomes.…”

mentioning

confidence: 99%

Exosomes function in antigen presentation during an in vivo Mycobacterium tuberculosis infection

Smith

Cheng

Bryant

et al. 2017

Sci Rep

102

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Mycobacterium tuberculosis-infected macrophages and dendritic cells are limited in their ability to present antigen to CD4+ T cells suggesting that other mechanism of antigen presentation are driving the robust T cell response observed during an M. tuberculosis infection. These mechanisms could include antigens present in apoptotic bodies, necrotic debris, exosomes or even release of non-vesicular antigen from infected cells. However, there is limited data to support any of these mechanisms as important in driving T cell activation in vivo. In the present study we use Rab27a-deficient mice which show diminished trafficking of mycobacterial components to exosomes as well as M. tuberculosis strains that express recombinant proteins which traffic or fail to traffic to exosomes. We observed that exosomes released during a mouse M. tuberculosis infection contribute significantly to its T cell response. These finding imply that exosomes function to promote T cell immunity during a bacterial infection and are an important source of extracellular antigen.

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The role of Rab27a in the regulation of neutrophil function

Cited by 32 publications

References 72 publications

Molecular mechanisms regulating secretory organelles and endosomes in neutrophils and their implications for inflammation

Molecular mechanisms regulating secretory organelles and endosomes in neutrophils and their implications for inflammation

Filifactor alocis Promotes Neutrophil Degranulation and Chemotactic Activity

Exosomes function in antigen presentation during an in vivo Mycobacterium tuberculosis infection

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