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Noor et al. Neuroimmunol Neuroinflammation 2019;6:10 I http://dx.doi.org/10.20517/2347-8659.2019.18 Page 25 of 32

Table 1. A brief summary of changes in immune factors following CCI and BIRT377 treatment
Male Female
Tissue Regions Immune Parameters # ## # ##
CCI CCI+ BIRT377 CCI CCI+ BIRT377
Sciatic Nerve CCL2 Up Down Up*
(Ipsilateral) IL-1β Up Down Up* Down
TNF Up Down Up Down
IL-10 Up Up* Up
TGFβ-1 Up Up* Up
CD11b Up Down Up*
CD3 Up Down Up
FOXP3 Up Up Up
IL-17A Up Up* Down
DRGs (Ipsilateral) CCL2 Up Up
IL-1β Up Down Up* Down
TNF Up Down Up
IL-10 Up Up
FOXP3 Up
Lumbar Spinal Cord CCL2 Up Up* Down
(Ipsilateral) IL-1β Up
TGFβ-1 Up Up
IL-10 Down Up Down Up
FOXP3 Up* Down
IL-17A Up* Down
GFAP Up Down Up
TMEM119 Up Up
Lumbar spinal Cord CCL2 Down
(Contralateral) IL-1β
TGFβ-1
IL-10 Up Down
FOXP3
GFAP Up Down Up* Down
TMEM119 Up Up
#
##
*Fold changes were significantly different in males versus females. Comparison between Sham+Veh and CCI+Veh, comparison
between CCI+Veh and CCI+BIRT377
Schwann cells (e.g., undergoing myelin degeneration), followed by circulating leukocytes recruited in
response to injury . CCL2 signaling recruits monocytes, neutrophils and a subset of T cells [18,91,92] . We
[7]
observed greater induction of SCN CCL2, along with greater SCN CD11b levels in males than females
during neuropathy. These data, in combination with greater SCN IL-1β production in males suggest greater
monocyte/macrophage-driven immune responses in males than females.

Though we detected T cell recruitment in both sexes, the critical finding was in detecting a T cell
differentiation bias toward a proinflammatory status that was significantly greater in females than males.
Moreover, responses to BIRT377 in females were robustly anti-inflammatory. For example, while an
induction of SCN FOXP3 (transcription factor in Tregs for IL-10 and TGF-β1) was detected from both
neuropathic males and females, BIRT377 induced additional increases only in SCNs of females with no
change in FOXP3 levels in males. Even more striking were the robust levels of SCN IL-17A of neuropathic
females compared to males, with profound blunting of IL-17A in pain reversed females relative to pain-
reversed males [Figure 4A to F]. These data indicate that females mount stronger proinflammatory T
cell responses following nerve injury compared to males despite an abundance of peri-sciatic T cells (as
indicated by CD3, global T cell marker) present in both males and females. Moreover, the striking FOXP3
increase and simultaneous IL-17A decrease predominantly in female SCN suggests that BIRT377 favors
targeting T cells derived from females than from males.