Bladder outlet obstruction (BOO) is a common problem that can affect bladder structure and function. Currently, there is no effective drugs available to prevent BOO-induced remodeling. Previous reports have demonstrated that the pathogenesis of BOO is associated with macrophage infiltration and polarization, which is physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) activation. Here we utilized a highly selective CSF-1R inhibitor, GW2580, to determine its preventive effects on BOO-induced remodeling.
A total of 24 Sprague-Dawley rats were randomly divided into sham, BOO + vehicle, and BOO + GW2580 group. GW2580 or vehicle control was administrated by oral gavage at daily doses of 40 mg/kg for 6 weeks. Bladder samples were collected for histopathology, immunohistochemistry, immunofluorescence, western blotting, and flow cytometry analysis.
Our results demonstrated that bladder fibrosis was ameliorated by GW2580 compared with the vehicle group (22.01% ± 5.13% vs. 32.15% ± 7.24%, p < 0.01). Furthermore, treatment with GW2580 induced an inhibition of macrophage infiltration (4.41% ± 1.28% vs. 13.57% ± 3.42%, p < 0.001) and M2 macrophage polarization (10.67% ± 4.15% vs. 28.59% ± 6.38%, p < 0.001). There was also a decrease of profibrotic F4/80+  α-smooth muscle actin+ (α-SMA+ ) macrophage to myofibroblast transition (9.11% ± 2.58% vs. 17.33% ± 4.01%, p < 0.001) and CD163+ TGF-β1+ cells (7.68% ± 2.10% vs. 14.17% ± 4.09%, p < 0.01) in the GW2580 group when compared with the vehicle group.
In summary, our findings showed that GW2580 is a worthwhile candidate for a follow-up study to test in the treatment of BOO-induced remodeling.
© 2022 Wiley Periodicals LLC.

Traumatic spinal cord injury (SCI) results in upregulation of chondroitin sulfate proteoglycans (CSPGs) by reactive glia that impedes repair and regeneration in the spinal cord. Degradation of CSPGs is known to be beneficial in promoting endogenous repair mechanisms including axonal sprouting/regeneration, oligodendrocyte replacement, and remyelination, and is associated with improvements in functional outcomes after SCI. Recent evidence suggests that CSPGs may regulate secondary injury mechanisms by modulating neuroinflammation after SCI. To date, the role of CSPGs in SCI neuroinflammation remains largely unexplored. The recent discovery of CSPG-specific receptors, leukocyte common antigen-related (LAR) and protein tyrosine phosphatase-sigma (PTPσ), allows unraveling the cellular and molecular mechanisms of CSPGs in SCI. In the present study, we have employed parallel in vivo and in vitro approaches to dissect the role of CSPGs and their receptors LAR and PTPσ in modulating the inflammatory processes in the acute and subacute phases of SCI.
In a clinically relevant model of compressive SCI in female Sprague Dawley rats, we targeted LAR and PTPσ by two intracellular functionally blocking peptides, termed ILP and ISP, respectively. We delivered ILP and ISP treatment intrathecally to the injured spinal cord in a sustainable manner by osmotic mini-pumps for various time-points post-SCI. We employed flow cytometry, Western blotting, and immunohistochemistry in rat SCI, as well as complementary in vitro studies in primary microglia cultures to address our questions.
We provide novel evidence that signifies a key immunomodulatory role for LAR and PTPσ receptors in SCI. We show that blocking LAR and PTPσ reduces the population of classically activated M1 microglia/macrophages, while promoting alternatively activated M2 microglia/macrophages and T regulatory cells. This shift was associated with a remarkable elevation in pro-regenerative immune mediators, interleukin-10 (IL-10), and Arginase-1. Our parallel in vitro studies in microglia identified that while CSPGs do not induce an M1 phenotype per se, they promote a pro-inflammatory phenotype. Interestingly, inhibiting LAR and PTPσ in M1 and M2 microglia positively modulates their inflammatory response in the presence of CSPGs, and harnesses their ability for phagocytosis and mobilization. Interestingly, our findings indicate that CSPGs regulate microglia, at least in part, through the activation of the Rho/ROCK pathway downstream of LAR and PTPσ.
We have unveiled a novel role for LAR and PTPσ in regulating neuroinflammation in traumatic SCI. Our findings provide new insights into the mechanisms by which manipulation of CSPG signaling can promote recovery from SCI. More importantly, this work introduces the potential of ILP/ISP as a viable strategy for modulating the immune response following SCI and other neuroinflammatory conditions of the central nervous system.