M.R. Galdiero1, E. Ciaglia2,
J. Dal Col2
1Department of Translational Medical Sciences and
Center for Basic and Clinical Immunology Research (CISI), University of
Naples Federico II, Naples, Italy; WAO Center of Excellence, Naples,
Italy; Institute of Experimental Endocrinology and Oncology (IEOS),
National Research Council, Naples, Italy
2Department of Medicine, Surgery and Dentistry ”Scuola
Medica Salernitana”, University of Salerno, Salerno, Italy
Corresponding author: Jessica Dal Coljdalcol@unisa.it
IL-17 has emerged as an important cytokine in protecting the host from
mucosal infections, but also as a pathogenic determinant and therapeutic
target in numerous autoimmune and inflammatory diseases (e.g. psoriasis,
psoriatic arthritis and ankylosing spondylitis, inflammatory bowel
disease and multiple sclerosis) (1). The
IL-17 family includes six members (IL-17A to IL-17F) that act through
the IL-17 receptors (1). The most studied
IL-17A, as well as IL-17F, binds to IL-17RA and IL-17RC resulting in
heterodimerization. Currently IL-17A, IL-17F, IL-17RA or IL-23, a
cytokine produced by innate immune cells that promotes expansion of Th17
cell populations, are targetable by monoclonal antibodies (mAbs). These
mAbs have been approved for the treatment of different autoimmune
diseases, most notably psoriasis, where their efficacy has outperformed
conventional non-steroidal anti-inflammatory and tumor necrosis factor
(TNF) blocking drugs. However, clinical trials and real-life experience
have shown an increase in fungal and bacterial upper respiratory tract
infections in patients treated with mAbs that block IL-23/IL-17
signaling. Accordingly, single nucleotide polymorphisms in genes
encoding IL-17A, IL-17RA, IL-17RC, IL-23, or NF-κB activator 1 (ACT1, an
adapter protein downstream of the IL-17R) which abrogate cellular
responsiveness to IL-17A, were associated with susceptibility to chronic
mucocutaneous candidiasis (CMC), a persistent infection of the skin,
nails, and/or mucous membranes with commensal Candida species
(2). So new effective targeted approaches
in IL-17 signaling are desirable.
Knizkova and colleagues identified a new adaptor molecule involved in
the IL-17/IL-17R cascade (3). Through
murine and human cell models, the authors found that CMTM4 (CKLF Like
MARVEL Transmembrane Domain Containing 4) constitutively bound to the
subunit IL-17RC becoming integral part of the IL-17R signaling complex
(IL-17RSC) upon IL-17A stimulation. CMTM4 promoted the surface
expression of IL-17RC by regulating posttranslational modifications,
especially IL-17RC glycosylation and trafficking to trans-Golgi up to
plasma membrane. CMTM4 was required for the recruitment of adapter ACT1,
for the activation of p38, JNK and transcription of genes encoding
proinflammatory cytokines upon IL-17A stimulation (Figure 1A).
Keratinocytes from the tail of Cmtm4−/− mice specifically express
lower levels of IL-17RC respect to Cmtm4+/+mice (Figure 1B). In vivo , when imiquimod (IMQ) was applied on
the ears or shaven backs of Cmtm4−/− mice, they
developed less severe psoriatic lesions and lower local expression of
IL-17A target genes compared to Cmtm4+/+ mice
(Figure 1C). However, in a MOG-induced model of experimental autoimmune
encephalomyelitis (EAE), Cmtm4−/− mice
displayed an only slightly milder EAE progression compared toCmtm4+/+ littermates, and the difference was
not statistically significant (Figure 1D). Overall, CMTM4 regulated
IL-17A signaling in vivo and mediated psoriasis, while it had
only a limited role in EAE. These apparently controversial results can
be explained by the fact that EAE pathology is not exclusively driven by
IL-17 and Th17 cells, but other cytokines and cells, including CD8+ T
cells and Th1 cells, fibroblasts, pericytes and astrocytes may be
involved (4,5). Indeed, as it displayed a relatively broad tissue
distribution, CMTM4 might finely tune the expression of other proteins,
not strictly connected to the immune compartment where CMTM4 is missing,
influencing the EAE disease course (5).
Accordingly, anti-IL-17 mAb treatment significantly reduced clinical
scores when administered at induction but not after clinical symptom
onset in the EAE model (6). This because
while IL-17 is required to trigger inflammation, it is superfluous in
the effector stage of the disease (6).
These aspects could further explain the mild effects of the lack of
CMTM4 on EAE pathogenesis.
In summary, the study by Knizkova and colleagues adds a new piece in the
puzzle of IL-17/IL-17R pathway, since highlights CMTM4 as an essential
subunit of the IL-17R, required for the IL-17R signaling. Given its role
in mediating IL-17A-induced responses, CMTM4 could represent a potential
new target for the therapy of IL-17A-mediated autoimmune diseases. On
the other hand, it is necessary to take into consideration that CMTM4
increases stability of PD-L1 protein, thus targeting CMTM4 could impair
PD-1/PD-L1 axis as well. Moreover, Cmtm4 could also represent
another putative gene whose defects or SNPs could account for
unexplained increased susceptibility to CMC.