A role for Rab27 in neutrophil chemotaxis and lung recruitment

Abstract

BackgroundNeutrophils are a critical part of the innate immune system. Their ability to migrate into infected or injured tissues precedes their role in microbial killing and clearance. We have previously shown that Rab27a can promote neutrophil migration by facilitating uropod release through protease secretion from primary granule exocytosis at the cell rear. Rab27b has been implicated in primary granule exocytosis but its role in neutrophil migration has not been investigated.ResultsHere we found Rab27b to be expressed in bone marrow derived neutrophils and Rab27b knockout (Rab27b KO) along with Rab27a/b double knockout (Rab27DKO) neutrophils exhibited impaired transwell migration in vitro in response to chemokines MIP-2 and LTB4. Interestingly, no additional defect in migration was observed in Rab27DKO neutrophils compared with Rab27b KO neutrophils. In vivo, Rab27DKO mice displayed severe impairment in neutrophil recruitment to the lungs in a MIP-2 dependent model but not in an LPS dependent model.ConclusionsThese data taken together implicate Rab27b in the regulation of neutrophil chemotaxis, likely through the regulation of primary granule exocytosis.

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

“…Thus, proper trafficking of vesicular compartments in neutrophils is important for migration. In agreement with this, migration of Rab27a‐KO neutrophils was found to be defective both in vitro and in vivo when treated with the neutrophil chemoattractant protein MIP‐2 . Impaired neutrophil migration was also reported in neutrophils from a few patients with Griscelli syndrome, where the neutrophils showed defective migration compared with neutrophils from healthy donors .…”

“…In vitro, the Rab27a‐KO neutrophils exhibit a defect in uropod retraction, as a consequence of a defect in serine protease release in the absence of Rab27a . Similarly, Rab27b‐KO neutrophils show impaired neutrophil migration in vitro to MIP‐2 and LTB4 and in an in vivo model of lung injury with intranasally delivered MIP‐2 . The defect observed in Rab27b knockout mice could possibly be due to impaired primary granule exocytosis observed in these neutrophils …”

Regulation of tissue infiltration by neutrophils

“…ATF3-deficient neutrophils displayed defective chemotaxis, which was associated with reduced expression of TIAM2, which is known to regulate Rac1-dependent focal adhesions and cell motility [39]. Neutrophil lung infiltration is also promoted by the GTPase Rab27b, which contributes to neutrophil migration in response to chemoattractants, such as CXCL2 (also designated macrophage inflammatory protein-2) and leukotriene B4 (LTB4) [40]. Interestingly, CXCR2-mediated chemotaxis of neutrophils is dependent on the presence of transient receptor potential channel family 6 (TRPC6), which regulates signaling downstream of the CXCR2 receptor [41].…”

Genetic deletion of Rab27B in pancreatic acinar cells affects granules size and has inhibitory effects on amylase secretion

“…It has been suggested that Rab27B plays a positive role to mediate secretion in pancreatic acinar cells as well as in many other cell types, with most of the evidence provided by overexpression of constitutively active or dominant negative forms of Rab27B protein [5,7]. In some secretory cells, Rab27B has been shown to be functionally redundant to Rab27A and in others to regulate secretion differently than Rab27A [8,9,10,11]. Rab3GEP/MADD was shown to be a non-redundant GEF for Rab27A activation in melanocytes [12] as well as a GEF for all four Rab3 isoforms [13], indicating that Rab27 proteins are closely co-regulated with Rab3 proteins.…”