Abstract
Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophil-specific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3F-mediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution.
Highlights
Effective host responses to injury and infection require both rapid recruitment of neutrophils into tissues and timely inflammation resolution
In tissue sections of surgically resected chronic obstructive pulmonary disease (COPD) lung, we identified staining for SEMA3F, and the coreceptor neuropilin 2 (NRP2) (Figure 1A), with NRP2 localized to the recruited CD66b+ myeloid cell populations (Figure 1B)
We identify a mechanism by which inflammatory cells can deliver a neutrophil-specific retention signal to the injury site in the form of a secreted axon guidance molecule, SEMA3F
Summary
Effective host responses to injury and infection require both rapid recruitment of neutrophils into tissues and timely inflammation resolution. Less focus has been placed on mechanisms by which viable neutrophils may be retained within the inflammatory site and contribute to the ongoing inflammation, yet this may be of particular therapeutic importance given the dominance of viable neutrophil numbers in inflamed tissue, even during the resolution phase of the innate immune response. Essential for neutrophil recruitment to the injury site and an effective innate immune response, is critically dependent upon polarization of the cell. Tubule assembly and activation of key regulators of the actin cytoskeleton, including Rho and Rac [2,3,4] These pathways are, unsurprisingly, well conserved across cell populations in which directed migration of cells is of critical importance, for instance, axonal migration or angiogenesis [5,6,7]. Given the parallels to directed migration in other systems, we asked whether proteins previously shown to regulate either axon repulsion or attraction and displaying regulated expression in immune cells may be important in signaling neutrophil retention within inflamed tissues and have an impact on inflammation resolution
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call