Overexpression and activation of colony‐stimulating factor 1 receptor in the SIV/macaque model of HIV infection and neuroHIV

Abstract

In the present study, we investigated whether colony‐stimulating factor 1 receptor (CSF1R) is expressed on brain macrophages and microglia in the human and macaque brain and whether it is upregulated and activated after lentivirus infection in vivo and contributes to development of encephalitic lesions. We examined, using multi‐label and semi‐quantitative immunofluorescence microscopy, the protein expression level and cellular localization of CSF1R in brain tissues from uninfected controls and SIV‐infected adult macaques with or without encephalitis and also from uninfected controls, HIV‐infected encephalitic subjects and virally suppressed subjects. In the normal uninfected brain, CSF1R protein was detected only on microglia and brain macrophages but not on neurons, astrocytes or oligodendrocytes. Microglia constitutively expressed CSF1R at low levels, and its expression was largely unchanged in non‐encephalitic and encephalitic animals. Brain macrophages, including perivascular macrophages (PVMs), expressed higher levels of CSF1R compared to microglia. Interestingly, we found significantly increased expression of CSF1R on the infected PVMs and lesional macrophages in the brains of encephalitic macaques. Moreover, the per cell expression of CSF1R determined by its mean pixel intensity (MPI) correlated positively with the MPI of SIV Gag p28 in SIV‐infected PVMs. Using phosphorylated CSF1R at tyrosine residue 723 and phosphorylated signal transducer and activator of transcription 5 at tyrosine reside 694 as markers for CSF1R activation, we found selective activation of CSF1R signaling in infected brain macrophages in encephalitis. We also found colocalization of CSF1R and its ligand CSF1 in PVMs and lesional macrophages in the brains of encephalitic macaques and humans. Notably, elevated brain CSF1R expression was found in virally suppressed subjects. These findings point to opportunities for developing a specific approach targeting infected brain macrophages, with several brain‐penetrant CSF1R inhibitors that are available now, in order to eliminate central nervous system macrophage reservoirs, while not affecting resting uninfected microglia and PVMs that show no CSF1R activation.

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

“…CSF1 is a cytokine of the mononuclear phagocytic system that is upregulated in a variety of CNS diseases, such as AD [46], EAE [47], and neuro HIV [23]. The biological effects of CSF1 are mediated by CSF1R, which is crucial in promoting the migration, proliferation, differentiation, survival, and polarization of macrophagelineage cells.…”

“…CSF1R is essential for microglia viability [15,20], which not only regulates the development, proliferation, and maintenance of microglia but also plays a major role in neuroinflammation [21,22]. Moreover, the expression and activity of CSF1R are increased after brain damage [15,23]. Wlodarczyk et al reported that stimulation of CSF1R by recombinant mouse CSF1 could induce the expansion of CD11c positive microglia, leading to improvement of EAE symptoms and less demyelination [24].…”

Role of macrophages in HIV pathogenesis and cure: NIH perspectives

“…Several potential targets and approaches have been investigated by NIMH supported investigators to eliminate myeloid reservoirs. Irons et al 72 . demonstrated colocalization of CSF1R and its ligand CSF1 in perivascular macrophages in the brains of encephalitic macaques and humans (virally suppressed).…”

“…Several potential targets and approaches have been investigated by NIMH supported investigators to eliminate myeloid reservoirs. Irons et al 72 demonstrated colocalization of CSF1R and its ligand CSF1 in perivascular macrophages in the brains of encephalitic macaques and humans (virally suppressed). These findings point to opportunities for developing a specific approach, targeting infected brain macrophages, with several brain penetrant CSF1R inhibitors that are available now, to eliminate central nervous system macrophage reservoirs.…”

“…These findings point to opportunities for developing a specific approach, targeting infected brain macrophages, with several brain penetrant CSF1R inhibitors that are available now, to eliminate central nervous system macrophage reservoirs. 72 Cunyat et al 73…”