Chemokine ligand 7 ( CCL 7) and innate immune cells in psoriasis: beyond redundancy

The role of chemokines as key factors in the attraction and activation of innate and adaptive immune cells has received growing attention in several chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel diseases and in the most frequent chronic inflammatory skin diseases, namely psoriasis and atopic dermatitis (AD) 1, 2. Chemokines are small peptides subclassified in C, CC, CXC and CX3C depending on the intervals between key cysteine residues 2. In a study published in a recent issue of the journal, Brunner et al. report the epidermal and dermal upregulation of CCL7 (chemokine ligand 7) in psoriatic skin both at the transcription and the protein levels, while faint CCL7 expression was detected in lesional skin from AD patients 3. This latter CCL7 is known to bind with various affinities to chemokine receptors CCR1, CCR2, CCR3, CCR5 and to the atypical decoy receptors DARC and D6 4. Starting from former observations in human psoriasis, with clear evidences for keratinocytes and blood microvascular blood endothelial cells as predominant sources of CCL7, Brunner et al. performed elegant in vivo experiments in an imiquimod-induced psoriasis-like mouse model to demonstrate that inhibiting CCL7 interactions leads to decreased skin inflammation associated with decreased dermal recruitment of macrophages and myeloid dendritic cells as well as to a lesser extent of neutrophils, while T-cell infiltrate remains unchanged. These results emphasize the key chemoattracting function of CCL7, previously named macrophage chemoattracting protein-3 (MCP3), towards major innate immune cell subsets, and provide additional support to the established hypothesis of a crucial contribution of the innate skin immune system in psoriatic inflammation (Fig. 1). Likewise, studies performed in the imiquimod-mouse model by Brunner et al. mirror previous observations that the innate immune system, more than T cells, is mandatory for the induction of severe skin inflammation in this disease model 4. Also of interest are experiments showing the stimulatory impact of the inflammatory cytokines IL-1ß and interferon-γ on the transcriptional expression of CCL7 in primary keratinocytes 3. In view of previous evidences that another member of the IL-1 family, the IL-36 pathway, is critical for skin inflammation in imiquimod-treated mice and also in pustular psoriasis, a rare but severe clinical variant, it would be interesting to investigate the impact of IL-36 agonists on CCL7 expression by human keratinocytes and dermal endothelial cells 4, 5. Also, the rapid decrease of CCL7 expression observed after the onset of tumor necrosis alpha blockade supports the impact of complex interactions between inflammatory pathways, not necessarily on a cell autonomous mode. Altogether, these data provide additional support for the key role of inflammatory macrophages, mDCs and neutrophils in psoriasis inflammation, while not ruling out an important contribution of the adaptive immune cell subsets, in this case predominantly TH1 and TH17 cells. Likewise, the observation that CCL7 inhibition leads to decreased IL12/23p40 transcriptional expression highlights the complex interplay between CCL7 and both innate and adaptive immune responses. Another remarkable characteristic of CCL7 among the macrophage-attracting chemokines is its plasticity towards monocytes and macrophage subpopulations, as shown by its ability to attract the proinflammatory M1, as well as the anti-inflammatory M2 subsets, raising a pivotal role for this chemokine in the regulation of cutaneous macrophage-dependent innate immune responses 6. In line with these recent insights, it will be interesting to track the expression of both CCL7 and its receptors in different macrophage and monocyte-derived cell subsets at different stages of psoriasis progression, for example formation and spontaneous regression. Therefore, a possible dual role of this chemokine in the attraction and immunomodulation of monocytes and macrophage subsets in patients can be elucidated. This in particular applies to inflammatory CD163+ macrophages, which have been associated with tissue destruction during psoriasis progression 7. Another temptative in vivo regulatory mechanisms for CCL7-dependent inflammation in psoriasis are the interaction of D6 decoy receptor, which has been poorly addressed in human skin so far. One more appealing aspect of CCL7 is its well-established role in cardiovascular arterial ischaemic disease. Accordingly, an increased plasma level of CCL7 has been identified as a prognostic factor for relapse in myocardial infarction (MI), an observation that is in keeping with its known proliferative effect on smooth muscle cells 8. Indeed, it is highly likely that factors accounting for the increased prevalence of cardiovascular comorbidities in severe psoriasis are not univocal and complex, but represent a common pattern of inflammatory chemokines in the atherosclerotic and psoriatic plaques. This observation is giving rise to a new hypothesis regarding shared patterns of inflammatory versus immunoregulatory innate immune cell subsets in the skin and the arterial wall. Furthermore, previous reports of ameliorated arterial disease in a rat model of arterial injuries by inhibiting inflammatory CC chemokine ligand–receptor interactions, including binding of CCL7 to its receptors, have opened new therapeutic perspectives for patients with both atherosclerotic disease and plaque psoriasis. In line with this, clinical trials have been conducted in humans with cardiovascular ischaemic disease, recently 9. Finally, recent advances on the privileged contribution of CCL7 to psoriasis pathogenesis provide more arguments to question the large redundancy among the chemokine network, which is known for a long time. Although a lot remain to be explored about the role of CCL7 across different skin diseases, current evidence for its involvement in psoriasis inflammation opens appealing perspectives. The author has no conflict of interest to declare.